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. The chemokine monokine induced by interferon-γ (Mig) is involved in the recruitment of inflammatory cells and liver injury during hepatitis B virus (HBV) infection. HBV protein X contributes to Mig expression in vitro by activation of nuclear factor (NF)-κB; however, the molecular mechanisms by which HBV induces Mig expression in vivo are unknown. In this paper, we established a mouse model for HBV study by tail vein injection of HBV genome-containing adenovirus vectors. Host immune response to the secreted hepatitis B surface antigen and e antigen was detected and serum alanine aminotransferase (ALT) was elevated at different time points. We also demonstrated that peripheral and intrahepatic Mig expression was increased after Ad-HBV infection. This was followed by inflammatory cell migration and formation of inflammatory foci in the liver. In addition, NF-κB p65 subunit translocated from the cytoplasm to the nucleus, and phosphoinositide 3-kinase/Akt, extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) were to some extent phosphorylated after HBV injection. Following tail vein injection of Mig siRNA/ in vivo-jetPEI-Gal complex, Mig expression was partially suppressed, inflammatory cell migration was inhibited, serum level of ALT were reduced. In conclusion, through NF-κB activation, HBV induced Mig expression in vivo, which recruited peripheral inflammatory cells to the liver and resulted in liver damage. Phosphorylation of phosphoinositide 3-kinase/Akt, ERK and JNK but not p38 might involved in the molecular mechanisms underlying HBV induced Mig expression in vivo. [ABSTRACT FROM AUTHOR]

Aim To determine the intravitreous concentration of monokine induced by interferon-γ (Mig) in patients with diabetic retinopathy (DR) and the relation between Mig and vascular endothelial growth factor (VEGF). Research design and methods Vitreous samples were obtained at the time of vitrectomy from 41 eyes of 38 DR patients (30 with active DR and 11 with inactive DR) and from 15 eyes of 15 non-diabetic patients who had macular disease (control subjects). Human Mig and VEGF were quantified using a FACS Caliber® flow cytometer. Results The vitreous concentration of Mig was increased significantly in patients with both active and inactive DR [148.0 (31.6–997.2; median range) and 82.3 (25.7–347.7) pg/ml, respectively] compared with control subjects [21.0 (5.2–74.3) pg/ml; P < 0.0001 and P < 0.001, respectively]. In DR patients, a significant ( P < 0.01) correlation was observed between vitreous concentrations of Mig and VEGF. Conclusion Our results suggest that Mig may play an important role in the pathogenesis of DR and works in consort with VEGF in the progression of pathological angiogenesis in DR. [ABSTRACT FROM AUTHOR]

Monokines play a major role in the regulation of hepatocyte functions. To document a possible in situ production of these mediators under physiological conditions, expression of IL-1β and of IL-6 genes was analyzed by in situ hybridization in four histologically normal human livers. We detected cells containing IL-1β mRNA or IL-6 mRNA in all cases. Cells expressing either the IL-1β gene or the IL-6 gene were found with equal frequency and were similarly distributed. Although present in all liver compartments, they were selectively enriched in portal areas, in which they were detected both in endothelial positions and in perivascular connective tissues. Few positive cells were observed in hepatic lobules, most of them being located in the walls of centrolobular veins, in an endothelial position. Subcapsular cells were also shown to express monokine genes. The location of positive cells and their pattern of labelling suggested that macrophages, fibroblasts and endothelial cells were the main cell populations expressing monokine genes. In contrast, Kupffer cells, biliary epithelial cells and hepatocytes did not express monokine genes. No marker of immune activation other than monokine gene expression was detected in these histologically normal livers. The expression of the IL-1β gene and of the IL-6 gene may be induced by gut-derived LPS, and could play a role in the modulation of hepatocyte function in normal liver. [ABSTRACT FROM AUTHOR]

The effects of human immunoglobulin preparations for intravenous use (IVIg) on in vitro-induced monokine production were studied. Individual peripheral blood monocytes, obtained from healthy blood donors, which produced interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) after in vitro stimulation, were identified by cytokine-specific monoclonal antibodies (mAb) and indirect immunofluorescence technique. Lipopylosaccharide (LPS) or Borrelia burgdorferi spirochetes (Bb) were used to induce TNF-α and IL-6 production in cultures. Peak synthesis occurred 2.5 hr after initiation of the cultures in tile majority of the monocytes, but not aL all in lymphocytes. The monocytes were identified by two-colour staining using a monocyte-specific mAb. IL-6 was produced by 64 ± 8% or 71 ± 9% (means±SD) of the non-IVIg-exposed monocytes after LPS or Bb stimulation, respectively (n = 12). A dose-dependent and significant reduction of the number of IL-6 producing cells was noted in the IVIg-supplemented cultures (P < 0.003). In these cultures 24 ± 12% or 29 ± 12% of the monocytes made IL-6 in response to LPS or Bb. Kinetic studies indicated a sustained significant inhibition of IL-6 production during 24 hr of culture (P < 0.001). In contrast, TNF-α synthesis was not inhibited by IVIg. LPS or Bb stimulation resulted in 47 ± 18% or 69 ± 7% TNF-α producing cells versus 48 ± 9% or 59 ± 8% in IVIg-supplemented cultures. These results indicate down-regulation of IL-6, but not TNF-α production, by IVIg. A direct antigen neutralization is an unlikely explanation for the divergent effects observed on monokine production after IVIg addition. [ABSTRACT FROM AUTHOR]

The proliferative response of guinea-pig thymocytes to co-mitogenic stimulation with phytohaemagglutinin and the guinea-pig interleukin I (IL-I )-like lymphocyte-activating monokine was lost by removing the cells that adhere to a Sephadex G-10 (G-10) column or the cells of low density in a Ficoll-Conray gradient. The diminished response in the G-10 non-adherent thymocyte or high-density thymocyte fraction was restored by the addition of a macrophage depleted G-10) adherent thymocyte fraction or a low-density. Ia-positive thymocyte fraction but not by the addition of peritoneal macrophages. These results suggest that the accessory cells which mediate the Increased responsiveness of thymocytes to the IL-1-like monokine existed in G-10 adherent cell fractions and the cells with this accessory function were not macrophages. The accessory cells were shown to be of low density, glass-non-adherent, G-l0-adherent, Fc receptor-negative, and Ia-positive. These results also suggest that the G-10-non-adherent and high-density thymocyte subpopulation, which is unresponsive or responds very little to the IL-1-like monokine by itself, acquires responsiveness to the monokine and proliferates by stimulation with the IL-1-like monokine and lectin in the presence of the accessory cells. [ABSTRACT FROM AUTHOR]

Objective: To elucidate the mechanism of the development of T cell infiltrates in the salivary glands of patients with Sjögren's syndrome (SS), we studied T cell-attracting chemokines and their receptors., Methods: The expression of the T cell-attracting chemokines, interferon-gamma (IFNgamma)-inducible 10-kd protein (IP-10; also called CXCL10), monokine induced by IFNgamma (Mig; also called CXCL9), and stromal cell-derived factor 1 (SDF-1; also called CXCL12), in salivary glands from SS patients was investigated by polymerase chain reaction-enzyme-linked immunosorbent assay (ELISA). Cells that produce chemokines and lymphocytes that express chemokine receptors were identified by immunohistochemistry. The production of IP-10 and Mig proteins by salivary epithelial cells in response to IFNgamma was determined by ELISA., Results: Expression of IP-10 and Mig messenger RNA (mRNA) was significantly up-regulated in SS salivary glands compared with normal salivary glands (both P < 0.01). There was no significant difference in SDF-1 mRNA expression between the SS and normal salivary glands. IP-10 and Mig proteins were predominantly expressed in the ductal epithelium adjacent to lymphoid infiltrates. Most of the CD3+ infiltrating lymphocytes in dense periductal foci expressed CXCR3, the receptor for IP-10 and Mig. IFNgamma induced the production of high levels of IP-10 and Mig proteins from cultured SS salivary epithelial cells., Conclusion: These findings suggest that IFNgamma stimulates the production of IP-10 and Mig in the SS ductal epithelium, and that IP-10 and Mig are involved in the accumulation of T cell infiltrates in the SS salivary gland. Chemokines or chemokine receptors could be a rational new therapeutic target in SS.

Objective: To investigate both the involvement of chemokines in general and the relative importance of specific chemokines in rheumatoid arthritis (RA), we characterized the effect of the monokines tumor necrosis factor alpha (TNF alpha) and interleukin-1 beta (IL-1 beta) on the synthesis of neutrophil-activating factors by synovial fibroblasts isolated from the joints of patients with RA., Methods: Neutrophil-stimulating activity was assessed by determining intracellular calcium mobilization. IL-8 synthesis and secretion was assessed by specific enzyme-linked immunosorbent assay, and IL-8 messenger RNA (mRNA) levels were determined by Northern blot., Results: Treatment of synovial fibroblasts with IL-1 beta and TNF alpha resulted in the production of an activity which induced intracellular calcium mobilization in peripheral blood neutrophils. The 2 monokines combined had a synergistic effect on the release of the neutrophil-stimulating activity. The effect of the 2 monokines required gene transcription and translation, and closely mimicked the pattern of IL-8 secretion induced in these cells by the monokines. We confirmed that the majority of the neutrophil-stimulating activity was IL-8 by 3 different approaches: cross-desensitization experiments with IL-8, melanoma growth-stimulatory activity, and neutrophil-activating peptide 2, stimulation of calcium mobilization in cells transfected with the IL-8 receptor complementary DNA, and inhibition of the activity following pretreatment of the supernatants with an anti-IL-8 antibody. TNF alpha and IL-1 beta induced a time- and dose-dependent release of immunoreactive IL-8. A synergistic effect of TNF alpha and IL-1 beta was also observed for both IL-8 production and accumulation of IL-8 mRNA., Conclusion: These results indicate that the monokines TNF alpha and IL-1 beta synergistically activate IL-8 expression and protein secretion by synovial fibroblasts, and that under these conditions, IL-8 appears to be the major neutrophil-activating factor released.

Supernatants from rat peritoneal macrophage cultures stimulated with bacterial products contain a Mr 36,000 factor that protects immature cortical thymocytes from loss of viability over a 4-hr incubation period in vitro. This effect could not be produced with purified transforming growth factor-β or recombinant interleukin-6 (IL-6). Further, the partially purified Mr 36,000 fraction was inactive in bioassays for IL-1 and tumour necrosis factor. Maximal production of the factor occurred 2 hr after the addition of 20 µg/ml of lipopolysaccharide, as assessed by the titre resulting in 100% protection of thymocytes in a viability assay. The detection of protective activity within 5 min after addition of the stimulant could be attributed to the release of intracellular stores but protein synthesis was required to account for the increasing titre up to peak levels. The titre fell rapidly after 2 hr so that activity could not be detected at 4 hr. This profile of release was refractory to repeated stimulation with lipopolysaccharide. Conjoint addition of lipopolysaccharide and indomethacin, did, however, allow release in response to subsequent challenge. Related to this finding, prostaglandin E2 completely inhibited the release of protective activity. [ABSTRACT FROM AUTHOR]

Peritoneal macrophages from normal mice which do not secrete interleukin 1 (IL 1) spontaneously release a factor with an approximate m.w. of 30,000-35,000. In contrast, in the presence of silica only IL 1 is produced. IL 1 as well as this macrophage-replacing factor (MRF) can restore the antibody response of macrophage-depleted spleen cells. IL 1, however, is the only one that has the capacity to increase the proliferation of thymocytes. In every strain of mice studied, including nude mice, we observed a spontaneous release of MRF and a silica-induced shift to the secretion of IL 1, except in lipopolysaccharide (LPS)-hyporesponsive C3H/HeJ mice. Macrophages from these mice are unable to secrete MRF spontaneously, or IL 1 when stimulated with silica. The kinetics of the secretion of MRF and IL 1 appear to be similar. Macrophages, regardless of whether they have been stimulated to secrete IL 1, produce an intracellular IL 1-like activity with an approximate m.w. of 15,000. In contrast, the intracellular PFC-restoring activity is widely distributed in the 15,000-60,000 m.w. range; one of these compounds could be related to IL 1 precursor and/or to MRF itself. Chromatofocusing and chromatography on Blue Trisacryl have led to a partial purification and resolution from a possible contamination by IL 1. Purified MRF induces, in conjunction with lymphokines, the differentiation of B cells into antibody-forming cells.

The effects of dietary supplementation with ω-3-polyunsaturated fatty acids (ω-3-PUFA) on the proliferative response of PBMC and on the secretion of monokines and arachidonic acid metabolites from PBMC and monocytes (Mo) from healthy subjects and patients with recent-onset insulin-dependent diabetes mellitus (IDDM) were examined. Three groups of eight to nine healthy individuals were randomized to either 2.0 g/day or 4.0 g/day of ω-3-PUFA devoid of vitamins A and D, or an isocaloric amount of placebo. Furthermore, eight patients with recentonset IDDM received 4.0 g/day of ω-3-PUFA. IL-lβ production and TNF-α secretion was determined before and after 7 weeks of treatment, and 10 weeks after withdrawal of treatment. Significant increases in platelet and PBMC membrane eicosapentaenoic acid was found in ω-3- PUFA-treated individuals. ω-3-PUFA treatment significantly reduced the content of IL-Iβ in lysates of PBMC, but did not affect PBMC or Mo secretion of IL-1β, TNF-α or prostaglandin E2 (PGE2) or PBMC leukotriene B4 (LTB4) secretion in healthy subjects or in IDDM patients. A significant inhibition of the PHA-stimulated, but not the spontaneous or PPD-stimulated, proliferative response of PBMC was observed in healthy and diabetic subjects treated with ω-3- PUFA. No correlation was found between PHA-stimulated PBMC proliferation and PBMC secretion of TNF-α and IL-lβ. There were no significant differences in the spontaneous or the PPD- or PHA-stimulated proliferative responses of PBMC between diabetic and healthy individuals at entry. We conclude that although dietary supplementation with 4.0 g/day of ω-3- PUFA inhibits the proliferation of PBMC and reduces IL-1β immunoreactivity in PBMC and Mo, it does not alter monokine, PGE2 or LTB4, secretion in healthy or IDDM subjects. [ABSTRACT FROM AUTHOR]

Aortic calcification—a marker of advanced atherosclerosis in large arteries—associates with cardiovascular mortality and morbidity. Little is known about the soluble inflamJarmatory profiles involved in large artery atherosclerosis. We investigated the correlation between aortic calcification in the abdominal aorta and cytokine levels in a cohort of peripheral artery disease patients. Aortic calcification index was measured from computed tomography exams and circulating cytokine levels were analyzed from blood serum samples of 156 consecutive patients prior to invasive treatment of peripheral artery disease. The study included 156 patients (mean age 70.7 years, 64 (41.0%) women). The mean ankle‐brachial index (ABI) was 0.64 and the mean aortic calcification index (ACI) was 52.3. ACI was associated with cytokines cutaneous T‐cell‐attracting chemokine CTACK (β 23.08, SE 5.22, p < 0.001) and monokine induced by gamma‐interferon MIG (β 9.40, SE 2.82, p 0.001) in univariate linear regression. After adjustment with cardiovascular risk factors, CTACK and MIG were independently associated with ACI, β 17.9 (SE 5.22, p < 0.001) for CTACK and β 6.80 (SE 3.33, p 0.043) for MIG. CTACK was significantly higher in the patients representing the highest ACI tertile (highest vs. middle, 7.53 vs. 7.34 Tukeys HSD p‐value 0.023 and highest vs. lowest tertile 7.53 vs. 7.29, Tukeys HSD p‐value 0.002). MIG was significantly higher in the highest tertile versus lowest (7.65 vs. 7.30, Tukeys HSD p‐value 0.027). Cytokines CTACK and MIG are associated with higher ACI, suggesting that CTACK and MIG reflect atherosclerotic disease burden of the aorta. This might further suggest the possible association with other cardiovascular morbidities. [ABSTRACT FROM AUTHOR]

The addition of picogram quantities of bacterial products to rat thymic cells in culture produced a doubling of the proliferative response to suboptimal levels of Concanavalin-A (Con-A). This effect was prevented by the depletion of adherent cells which comprised <0.1% of the total population. The response was restored by the addition of supernatants from peritoneal macrophages which had been stimulated 2 h previously with lipopolysaccharide. Treatment of these supernatants with phenylglyoxal, an inhibitor of interleukin-l (IL-1), did not prevent the stimulatory effect. Augmentation of the thymocyte proliferative response could also be achieved by the addition of a partially purified monokine of relative molecular weight (Mr) 36 000 which is biochemically and functionally distinct from IL-1 and by a monoclonal antibody which binds to a common determinant on the Ia molecule. Fractionation of the thymic cells on a density gradient yielded a buoyant population which accounted for the majority of the proliferative activity and a dense fraction which was poorly responsive to the mitogen. The addition of the monokine to this latter fraction produced a significant increase in proliferation in response to Con-A. It is proposed that in the thymus, bacterial products stimulate thymic macrophages to release the Mr 36000 monokine which in turn stimulates the thymic epithelial cells to release products which promote the survival and maturation of immature thymocytes. This work has implications for the regulation of thymocyte maturation. [ABSTRACT FROM AUTHOR]

There is a marked decrease in the viability, in vitro, of dense, immature rat thy mocytes over a 4 h incubation period. The addition of a monokine of relative molecular weight 36 000 derived from cultured rat peritoneal macrophages which had been previously stimulated with lipopolysaccharide prevented these cells from dying. The early release of this factor, together with preliminary results of its physical and functional properties suggest that it is distinct from the well characterized monokines. The macrophage factor was found to bind in competition with a monoclonal antibody directed against a common determinant on the la antigen complex, but also to bind non-competitively with a monoclonal antibody to a strain-specific epitope on Ia. Based on the results of experiments using a fractionated thymic cell model, it would appear that this monokine binds to the la protein complex on the cell surface of thymic epithelial cells, causing them in turn to release an activity which is responsible for the survival of thymocytes. [ABSTRACT FROM AUTHOR]

HLA-class III region genes may be associated with susceptibility to insulin-dependent diabetes mellitus(IDDM). In this study an Neol polytnorphism of the tumour necrosis factor beta (TNF-α) gene, which is positioned next lo the tumour necrosis factor alpha (TNF-β) gene in the HLA class III region, was detected by restriction fragment length polymorphism (RFLP). This polymorphism has previously been reported to be located in the TNF-i gene. Caucasian HLA-DR3,4 heterozygous IDDM patients (n = 26) and DR-matched healthy controls (n= 19), as well as randomly selected IDDM patients (n = 27) and controls (n = 25) were studied. In addition four multiplex families (49 individuals) and eight HLA-non-identical sibpairs concordant for IDDM were analysed. The TNF-β gene RFLP analysis showed fragments of 5.5 kb and 10.5 kb, which behaved as alleles. in all groups there was a haplotype assignment of the TNF-β 5.5-kb allele to B8,DR3 haplotypes, and of the TNF-β 10.5-kb allele to B15,DR4-positive haplotypes. The allelic and genotypic frequencies differed between DR3,4 IDDM patients and DR3,4 controls, and the DR3,4 control group differed significantly from the randomly selected control group (P< 0.0079), In HLA-DR3,4-and DQw8-positive persons, the DR3 haplotypes carried the 10.5- kb allele three times more frequently in IDDM patients than in controls, suggesting that the 10.5- kb allele when present on DR3 haplotyes may contribute lo susceptibility to IDDM in DR3,4 heterozygous individuals. A contributory role of the 10.5-kb allelel in genetic IDDM susceptibility was supported by the sibpair analysis, in which all were TNF-β identical. Five were 10.5 kb homozygous. and the remaining three pairs were 5.5,10,5 kb heterozygous. Twenty-five healthy and eight newly diagnosed IDDM patients were randomly selected to study the Escherichia coli lipopolysaccharides (LPS)-purified protein derivate (tuberculin) (PPD)-, and phytohaemagglutinin (PHA)-stimulated monocyte (Mo) secretions of interleukin 1 beta(IL-lβ) and TNF-β in relation to the Ncol TNF-β gene polymorphism. The LPS-and PHA-stimulated Mo IL-lβ and TNF-α secretions were significantly lower for the TNF-β 5.5,10.5 kb heterozygous individuals than for TNF-β 10.5 kb homozygous individuals. Furthermore, the Mo IL-1β and TNF-α secretions of IDDM patients were significantly higher than the Mo secretions of TNF-β genotype-matched healthy controls. [ABSTRACT FROM AUTHOR]

AIM: To determine the intravitreous concentration of monokine induced by interferon-gamma (Mig) in patients with diabetic retinopathy (DR) and the relation between Mig and vascular endothelial growth factor (VEGF). RESEARCH DESIGN AND METHODS: Vitreous samples were obtained at the time of vitrectomy from 41 eyes of 38 DR patients (30 with active DR and 11 with inactive DR) and from 15 eyes of 15 non-diabetic patients who had macular disease (control subjects). Human Mig and VEGF were quantified using a FACS Caliber flow cytometer. RESULTS: The vitreous concentration of Mig was increased significantly in patients with both active and inactive DR [148.0 (31.6-997.2; median range) and 82.3 (25.7-347.7) pg/ml, respectively] compared with control subjects [21.0 (5.2-74.3) pg/ml; P < 0.0001 and P < 0.001, respectively]. In DR patients, a significant (P < 0.01) correlation was observed between vitreous concentrations of Mig and VEGF. CONCLUSION: Our results suggest that Mig may play an important role in the pathogenesis of DR and works in consort with VEGF in the progression of pathological angiogenesis in DR. [ABSTRACT FROM AUTHOR]

Background. Observational studies have suggested an association between inflammatory cytokines and Parkinson's disease (PD). This Mendelian randomization (MR) was conducted to further assess the causal correlations between inflammatory cytokines and PD. Methods. Genetic instruments associated with inflammatory cytokines were extracted from a large summary genome-wide association studies (GWAS) involving 8,293 European participants. Summary-level statistics for PD were obtained from a large-sample GWAS containing 17 studies that involved European participants. Causalities of exposures and outcomes were explored mainly using inverse variance weighted (IVW) method. Results. The IVW method indicated that basic fibroblast growth factor (FGFBasic), interleukin-2 (IL-2), and macrophage migration inhibitory factor (MIF) may be suggestively associated with the risk of PD (OR: 0.71, 95%CI: 0.52–0.96, P = 0.027; OR: 1.18, 95%CI: 1.01–1.38, P = 0.041; and OR: 1.23, 95%CI: 1.04–1.46, P = 0.018). In the reverse direction, monokine induced by interferon gamma (MIG), beta nerve growth factor (bNGF), interleukin-17 (IL-17), and interferon gamma (IFNg) are suggested to be the consequences of PD. Conclusion. Our MR analysis indicated that suggestive associations between circulating levels of FGFBasic, IL-2, and MIF and PD risk. In addition, MIG, bNGF, IL-17, and IFNg are more likely to be involved in the development of downstream PD. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented related to the Correlation between cerebrospinal fluid cell count and cerebrospinal fluid level of chemokine.

Background: This cross‐sectional study aimed to evaluate salivary concentrations of macrophage activation‐related chemokines and mitogen‐activated kinase kinase (MAPKK)‐degrading proteolytic activity in children and adolescents with and without type 1 diabetes mellitus (T1DM). Methods: A total of 122 children and adolescents (65 T1DM patients, 50.8% female, mean age:10.9 years; 57 systemically healthy controls, 36.8% female, mean age: 9.5 years) were included in the study. Salivary concentrations of interferon gamma inducible protein‐10 (IP‐10), monocyte chemoattractant protein (MCP)‐1, MCP‐2, MCP‐3, MCP‐4, macrophage‐derived chemokine (MDC), macrophage migration inhibitory factor (MIF), monokine induced by interferon gamma (MIG), and macrophage inflammatory protein‐1 alpha (MIP‐1α) were quantified using a bead‐based technique. MAPKK‐degrading proteolytic activity was detected using fluorescent peptide substrates. Results: The T1DM group had higher plaque index (PI%, p = 0.032) and bleeding on probing (BOP%, p = 0.045) scores, and lower decayed, missing, filled teeth (dmft/DMFT, p = 0.002) index scores compared to the healthy controls. Compared to the controls, salivary MCP‐1 (p = 0.007), MCP‐3 (p < 0.001), MIG (p = 0.007), and MIP‐1α (p = 0.033) concentrations were elevated whereas MCP‐4 concentrations decreased (p < 0.001) in the T1DM group. After adjusting for age, PI%, BOP%, and dmft/DMFT scores, significant differences in salivary concentrations of MIG (p = 0.033) and MIP‐1α (p = 0.017) were observed between the groups. Moreover, protease activities directed to the cleavage sites of MEK23‐18 (p = 0.001), MKK6b7‐22 (p = 0.007), MKK451‐66 (p = 0.005), MKK7b37‐52 (p = 0.034), and MKK7b69‐84 (p = 0.009) were elevated in the T1DM group. Conclusion: T1DM disrupts the salivary macrophage activation‐related chemokine profile and dysregulates proteolytic MAPKK cleavage. These findings can be an outcome of the impaired systemic immune response in T1DM. [ABSTRACT FROM AUTHOR]

Idiopathic granulomatous mastitis (IGM), a recurrent inflammation disease of the non‐lactating breast, has had an increasing clinical morbidity rate in recent years, and its complicated symptoms and unclear etiology make it challenging to treat. This rare benign inflammatory breast disease, centered on the lobules, represents the most challenging type of non‐puerperal mastitis (NPM), also known as non‐lactating mastitis. In this study, patients diagnosed with IGM (M, n = 23) were recruited as cases, and patients with benign control breast disease (C, n = 17) were enrolled as controls. Cytokine microarray detection measured and analyzed the differentially expressed cytokine factors between IGM and control patients. Then, we verified the mRNA and protein expression levels of the significantly changed cytokine factors using Q‐RT‐PCR, ELISA, western blot, and IHC experiments. The cytokine factor expression levels significantly changed compared to the control group. We observed a significant increase between IGM and control patients in cytokine factors expression, such as interleukin‐1β (IL‐1β), monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)‐1α, MIP‐1β, tumor necrosis factor receptor 2 (TNF RII). Then, we verified the expression of these top five dysregulated factors in both mRNA and protein levels. Our results demonstrated the cytokine map in IGM and indicated that several cytokines, especially chemokines, were associated with and significantly dysregulated in IGM tissues compared to the control group. The chemokine factors involved might be essential in developing and treating IGM. These findings would be helpful for a better understanding of IGM and offer valuable insights for devising novel diagnostic and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Interleukin Iβ (IL-lβ) and tumour necrosis factor alpha (TNF-α) may be pathogenetically important in insulin-dependent diabetes mellitus (IDDM), which is associated with genes of the HLA region. Since a regulatory role of HLA region genes on monokine production may exist, we looked for an association between the monokine and prostaglandin E2 (PGE2) responses of monocytes (Mo) from 20 healthy males (18-50 years) with HLA-DR types relevant for IDDM susceptibility and resistance (DR 1,2. DR1,3, DR1,4, DR3.4). Monokine assays were established and evaluated and the secretions of IL-1 β, TNF-α. and PGE2 measured in Mo cultures (2 h, 6 h, 20 h) prepared by endotoxin-free techniques and stimulated by low-dose E. coli lipopolysaccharides (LPS). There were no significant associations between Mo responses and HLA-DR phenotype. Likewise, Mo from DR2 (n = 5) and DR4 (n = 5) homozygous healthy males demonstrated no significant differences in monokine and PGE2 responses of Mo. In the HLA class III region a diallelic TNF-β gene Ncol polymorphism consisting of alleles of 5.5 kb and 10.5 kb was recently described and associated with susceptibility to autoimmune diseases including IDDM. We report that IL-1 β and TNF-α responses of Mo from TNF-β 10.5 kb homozygous healthy individuals were significantly higher than for TNF-β 5.5/10.5 kb heterozygotes. IL-1 β and TNF-α responses of Mo from males (18-35 years) with newly diagnosed (n = 10) and long-standing IDDM (n= 10) and from age- and HLA-DR-matched healthy males (n= 10) were studied. LPS, gamma interferon (IFN), and TNF-α-stimulated Mo cultures were investigated. No significant differences were found between Mo responses of IDDM patients and controls. IFN (1000 U/ml) in the presence of LPS significantly potentiated LPS-stimulated Mo TNF-α secretion and reduced the levels of IL-1 β immunoreactivity in Mo lysates. I FN and TNF-α did not have any effects on LPS-stimulated Mo secretion of IL-1β immunoreactivity. We conclude that Mo IL-1β and TNF-α production is normal in patients with recent-onset and long-standing IDDM. The interindividual differences in monokine responses may be accounted for by the diallelic human TNF-β gene polymorphism rather than by HLA class II genes. This observation may be important for understanding the association of certain H LA haplotypes with autoimmune phenomena and disease. [ABSTRACT FROM AUTHOR]

Altered host immune responses are considered to play a key role in the pathogenesis of acute lower respiratory infections (ALRI). The existing literature on cytokine responses in ALRI is largely focussed on adults from developed countries and there are few reports describing the role of cytokines in childhood ALRI, particularly in African or human immunodeficiency virus (HIV)‐infected populations. To measure systemic cytokine levels in blood plasma from young South African children with and without ALRI and with and without HIV to determine associations between cytokine responses and disease status and respiratory viral identification. Blood plasma samples were collected from 106 hospitalized ALRI cases and 54 non‐ALRI controls less than 2 years of age. HIV status was determined. Blood plasma concentrations of 19 cytokines, 7 chemokines, and 4 growth factors (epidermal growth factor, fibroblast growth factor‐basic, hepatocyte growth factor, and vascular endothelial) were measured using The Human Cytokine 30‐Plex Panel. Common respiratory viruses were identified by PCR. Mean cytokine concentrations for G‐CSF, interferon (IFN)‐γ, interleukin (IL)‐5, and MCP‐1 were significantly higher in ALRI cases than in nonrespiratory controls. Within the ALRI cases, several cytokines were higher in children with a virus compared with children without a virus. Mean cytokine concentrations for IFN‐α, IFN‐γ, IL‐4, IL‐5, IL‐13, tumour necrosis factor‐α, and MIP‐1α were significantly lower in HIV‐infected cases than in HIV‐uninfected cases, while IP‐10 and monokine induced by interferon‐γ were significantly higher in HIV‐infected cases than in HIV‐uninfected cases. Certain cytokines are likely to play an important role in the host immune response to ALRI. HIV‐infected children have impaired inflammatory responses to respiratory infections compared with HIV‐uninfected children. [ABSTRACT FROM AUTHOR]

Objective: Response to immunosuppression is highly variable in systemic sclerosis (SSc)–related interstitial lung disease (ILD). This study was undertaken to determine whether a composite serum interferon (IFN)–inducible protein score exhibits predictive significance for the response to immunosuppression in SSc‐ILD. Methods: Serum samples collected in the Scleroderma Lung Study II, a randomized controlled trial of mycophenolate mofetil (MMF) versus cyclophosphamide (CYC), were examined. Results were validated in an independent observational cohort receiving active treatment. A composite score of 6 IFN‐inducible proteins IFNγ‐inducible 10‐kd protein, monokine induced by IFNγ, monocyte chemotactic protein 2, β2‐microglobulin, tumor necrosis factor receptor type II, and macrophage inflammatory protein 3β) was calculated, and its predictive significance for longitudinal forced vital capacity percent predicted measurements was evaluated. Results: Higher baseline IFN‐inducible protein score predicted better response over 3 to 12 months in the MMF arm (point estimate = 0.41, P = 0.001) and CYC arm (point estimate = 0.91, P = 0.009). In contrast, higher baseline C‐reactive protein (CRP) levels were predictive of a worse ILD course in both treatment arms. The predictive significance of the IFN‐inducible protein score and CRP levels remained after adjustment for baseline demographic and clinical predictors. During the second year of treatment, in which patients in the CYC arm were switched to placebo, a higher IFN‐inducible protein score at 12 months showed a trend toward predicting a worse ILD course (point estimate = −0.61, P = 0.068), while it remained predictive of better response to active immunosuppression in the MMF arm (point estimate = 0.28, P = 0.029). The predictive significance of baseline IFN‐inducible protein score was replicated in the independent cohort (rs = 0.43, P = 0.028). Conclusion: A higher IFN‐inducible protein score in SSc‐ILD is predictive of better response to immunosuppression and could potentially be used to identify patients who may derive the most benefit from MMF or CYC. [ABSTRACT FROM AUTHOR]

Problem: We investigated if the PROGINS mutation increases the risk of hepatitis E virus (HEV) infection in liver transplant recipients. PROGINS was analyzed through KASP assay; HEV serologies assessed via enzyme‐linked immunosorbent assay and multiplex cytokine assays were evaluated in plasma with the ProcartaPlex human immunoassay. Seventy liver transplant recipients were evaluated, of which 23 (33%) were HEV immunoglobuln G (IgG)‐positive (HEV+). The frequency of PROGINS in the HEV+ group was 34%, compared with 14% in those that were HEV IgG negative (HEV−). Cytokine measurements in a sub‐set of samples from HEV+/PROGINS+ individuals showed decreased plasma levels of monokine induced by gamma interferon, a proliferation‐inducing ligand, and stem cell factor, as well as increased levels of eotaxin‐3 and interleukin‐31 compared with those HEV−/PROGINS− samples. Our findings suggest an association between the PROGINS mutation and seropositivity for HEV in liver transplant recipients with consequent distorted cytokine levels. Highlights: It is unclear why transplant recipients have an increased risk of HEV infection. We found an increased rate the PROGINS mutations liver transplant in HEV‐positive individuals. [ABSTRACT FROM AUTHOR]

Background: Biomarkers to objectively measure disease severity and predict therapeutic responses are needed in atopic dermatitis (AD). Objective: Primary aim: To identify biomarkers reflecting therapeutic response in patients with AD treated systemically. Secondary aims: (i) To identify a biomarker pattern predicting responsiveness to systemic treatment. (ii) To identify differences in expression of biomarker in filaggrin gene (FLG) mutation carriers vs. non‐FLG mutations carriers. Methods: Thirty‐eight severe AD patients treated with methotrexate or azathioprine participated. Serum levels of a proliferation‐inducing ligand, B‐cell activating factor of the TNF family, thymus and activation‐regulated chemokine (chemokine (C‐C motif) ligand 17) (TARC (CCl‐17)), interleukin‐1 receptor antagonist (IL‐1RA), interleukin‐1 bèta, IL‐4, IL‐6, IL‐7, IL‐8, IL‐9, IL‐10, IL‐12, IL‐13, IL‐18, IL‐31, interferon gamma, tumour necrosis factor alpha, vascular endothelial growth factor (VEGF), monokine induced by interferon gamma (chemokine (C‐X‐C motif) ligand 9), interferon gamma‐induced protein 10 (C‐X‐C motif chemokine Ligand 10), monocyte chemoattractant protein‐1 (chemokine (C‐C Motif) ligand 2), macrophage inflammatory protein‐1 beta (chemokine (C‐C motif) ligand 4), regulated on activation, normal T cell expressed and secreted (chemokine (C‐C motif) ligand 5), Cutaneous T‐cell‐attracting chemokine (chemokine (C‐C motif) ligand 27) (CTACK (CCL‐27)), thymic stromal lymphopoietin, IL‐5, interleukin‐1 alpha and granulocyte‐colony stimulating factor were analysed by ELISA and Luminex. The primary outcomes were differences in mean absolute change of SCORing Atopic Dermatitis (SCORAD) between groups after 12 weeks compared with baseline. Responders to treatment were defined by a SCORAD reduction in ≥50%. Buccal mucosa swabs were collected to determine FLG genotype status. Results: Thymus and activation‐regulated chemokine, CTACK, IL‐13 and VEGF showed a significant decrease after treatment with methotrexate or azathioprine. However, no decrease in individual cytokine levels was significantly correlated with a change in any of the outcome parameters. In addition, baseline biomarker levels were not significantly different between responders and non‐responders, and FLG and non‐FLG mutants showed similar biomarker profiles. Conclusion: Thymus and activation‐regulated chemokine and CTACK were confirmed as potential biomarkers. VEGF and IL‐13 have a potential value as well. Biomarkers could not be used to discriminate at baseline between responders and non‐responders, or FLG genotype status. [ABSTRACT FROM AUTHOR]

Background: Human peripheral blood mononuclear cells (PBMC) left in microcultures for 24 h without mitogen do not respond to subsequent stimulation with PHA. They regain reactivity if the native culture medium is absorbed with other party lymphocytes or partially replaced with the medium from a PHA-stimulated culture. The observations suggest that, during the incubation, some inhibitory agent had accumulated in the culture medium. Aim: The study was performed to determine the nature of the observed phenomenon in respect of the possible role of monocytes and their products IL-1 and IL-1 receptor antagonist (IL-1ra), and to test for immunodiagnostic purposes the significance of quantifying the lymphocyte response to delayed stimulation with PHA in patients suffering from inflammatory prosesses. Methods: Lymphocyte response to delayed stimulation with PHA, calculated as the lymphocyte-monokine interaction (LM) index, was determined in the microcultures of PBMC isolated from the blood of healthy donors or of patients with acute tonsilitis. The values of LM indices were compared with the ratios of IL-1ra/IL-1β concentration estimated by enzyme-linked immunosorbent assay method in the culture supernatants. The influences of exogenous IL1 β , IL-1ra, anti-IL1ra antibodies and antibiotic cefaclor on the monokine concentrations and on the values of LM index were tested. Results and conclusions: The results show that the level of lymphocyte response to delayed stimulation with PHA (LM index) is inversely proportional to the ratio of IL-1ra/IL-1β concentration in the culture. The low LM values at high IL-1ra/IL-1β ratios in PBMC cultures from healthy donors, reversed proportions found in patients' PBMC (acute tonsilitis), and the cefaclor-induced reduction of LM value with correlated increase of the IL-1ra/IL-1β ratio suggest that the LM assay may prove to be useful for immunodiagnostic purposes. [ABSTRACT FROM AUTHOR]

The secretions of interleukin 1 (IL-1), tumour necrosis factor a (TNF), and prostaglandin E2 (PGE;) of low-dose E. coli lipopolysaccharide (LPS)-stimulated human monocytes (Mφ) were investigated in an endotoxin (ET)-free milieu (<1.6 pg LPS/ml). Human Mφ cultures from nine healthy men were stimulated with 0, 12..5-500, and 250,000 pg LPS/ml as measured by a very sensitive Limulus test. The IL-1 activity was tested by the mouse costimulatory thymocyte (LAF) assay, which was thoroughly standardized and characterized (interassay variation 12-24%, intra-assay variation 3-7%). Spontaneous Mφ secretions of IL-1, TNF, and PGE2 were negligible, but 12.5 pg LPS/ml significantly stimulated the secretions of these Mφ products and the monokine responses to 500 and 250, 000 pg LPS/ml were almost in the same range. Il was demonstrated that the secretions of IL-l-TNF and TNF-PGE2 were strongly correlated. Pronounced interindividual differences in LPS responsiveness were demonstrated, and two low-responders, one of whom was HLA-DR 1,2-positive, were identified. Three first-degree relatives of the DRL,2-positive low-responder had similar low responses. Furthermore, Mφ cultures were prepared weekly for 4 weeks from four HLA-DR different men and the only DR2,2 homozygous individual had low monokine responses. In conclusion, stable interindividual differences in in vitro monokine and PGE; secretions of LPS-stimulated Mφ were demonstrated. It is suggested that HLA-DR2-positive individuals may be low responders. [ABSTRACT FROM AUTHOR]

Mononuclear cells obtained from human blood were mitogen or antigen activated in vitro in the presence or absence of FK506 or cyclosporin A (CsA). Cytokine production was studied at a single-cell level by ultraviolet (UV) microscopy of fixed permeabilized cells using cytokine-specific monoclonal antibodies (mAb). Phenotypic characterization of the monokine-producing cells was achieved by two-colour immunofluorescent staining. Cytokine production after antigen activation with Staphylococcus aureus enterotoxin A (SEA) was significantly reduced. FK506 or CsA inhibited SEA-induced tumour necrosis factor-alpha (TNF-α) production both in monocytes (P < 0.01) and in lymphocytes (P < 0.01), at a drug concentration of 1-25 ng/ml for FK506 and 100-500 ng/ml for CsA. Lymphocyte synthesis of intcrleukin-2 (IL-2), interferon-gamma (IFN-γ) and TNF-β after SEA activation was also significantly reduced by either of the drugs. In contrast, endotoxin-induced monokine production (TNF-α and IL-6) after lipopolysaccharide (LPS) stimulation was unaffected by FK506 or CsA even when added in concentrations as high as 1000 ng/ml. When the cells were stimulated by phorbol ester (phorbol 12-niyristatc 13-acetatc, PMA) plus calcium ionophore (ionomycin). FK506 and CsA inhibited, in a dose-dependent manner, the production of IL-2, IL-4, IL-5, IFN-γ and TNF-α. The 50% inhibitory concentration (IC50) for FK506 or CsA on the cellular synthesis of the various cytokines varied between 0.6 and 1.0 ng/ml and 20 and 60 ng/ml, respectively. Further stimulation by addition of anti-CD28 mAb to the cultures resulted in an augmented IL-2 and IFN-γ production which was resistant to both FK506 and CsA. This report delineates extensive similarities between the two drugs in mechanisms of immunosuppression by blockade of identical interleukin production. Depending on the mode of cell activation the two drugs inhibited not only cytokine production in lymphocytes but also antigen-induced monokine (TNF-α) production in macrophages, although the optimal immunomodulatory effect of FK506 was achieved at a concentration approximately 50-fold lower than that of CsA. [ABSTRACT FROM AUTHOR]

Treatment with human recombinant turnout necrosis factor-α (rTNFα) significantly enhanced resistance to Listeria monocytogenes infection in mice. The level of protection (which was dose-dependent and maximal at approximately 1·0 μg per mouse) was similar to that previously reported for the monokine rIL-1α, although somewhat greater amounts of rTNFα than rIL-1α were required. Combined administration of suboptimal concentrations of rTNFα and rIL-1α resulted in significant enhancement of resistance beyond that obtained with either monokine alone, whereas further increases in anti-listeria resistance were not observed at doses of rTNFα or IL-1α that were themselves capable of inducing substantial protection. Combined administration of rTNFα and rIL-1α was associated with a delay in onset and lessening in severity of the lymphopenia that accompanied L. monocytogenes infection. The reduced bacterial burden in the spleens and livers of mice treated with rTNFα and rIL-1α was associated with a more rapid decline in serum colony-stimulating activity. Peritoneal macrophages from rTNFα- and rIL-1α-treated listeria-infected mice did not demonstrate enhanced anti-listeria activity in vitro. These results provide further evidence for the potential benefits of rTNFα and other cytokines in promoting anti-bacterial resistance. They further suggest that use of combinations of cytokines is a strategy worthy of further consideration. [ABSTRACT FROM AUTHOR]

Background: The aim of this trial was to evaluate the cytokine, chemokine, and growth factor levels in peri-implant sulcular fluid (PISF) during healing and osseointegration at osteotomy sites prepared either with piezosurgery (PS) or drills.Methods: Fourteen patients having contralateral partial edentulism in the posterior maxilla were enrolled and 38 osteotomies were prepared. Implants were placed with one-stage surgery. Insertion torque, early healing index, probing depth and modified gingival and plaque indices and crestal bone loss (CBL) were measured. PISF was collected from each implant at weeks 2, 4, 8, 12, and 24 and were analyzed by a 30-Plex immunoassay. Data analysis employed Brunner-Langer method.Results: CBL values did not depend on osteotomy modality (P > 0.05). Eighteen molecules (interleukine (IL)-1β, granulocyte colony stimulating factor (G.CSF), IL-13, IL-6, IL-12, interferon (IFN)-γ, IFN-α, IL-2, IL-2 R, IL-8, macrophage inflammatory protein (MIP)-1α, MIP-1β, monocyte chemoattractant protein (MCP)-1, interferon gamma-induced protein (IP)-10, monokine induced by IFN-γ (MIG), epidermal growth factor (EGF), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF) showed time-dependent decrease (P < 0.05), but they were not treatment-dependent (P > 0.05). When values of weeks 4, 8, 12, and 24 were compared to week 2, it was found that all were highest at week 2 and decreased thereafter (P < 0.05). The decrease was significant at weeks 4 or 8 for multitude of molecules and was mostly sustained throughout the follow-up. Week 8 regulated on activation, normal T cell expressed and secreted (RANTES) values in PS group were lower in PS group compared to drill group (P < 0.05).Conclusions: Implants placed into osteotomies created with PS and drills are similar in terms of PISF biomarker changes during the osseointegration and wound healing period. When clinical and CBL parameters were taken into account together with the PISF molecular data it can be speculated that PS and conventional drill osteotomy have similar effects on peri-implant tissues on the biochemical, clinical and radiological levels. [ABSTRACT FROM AUTHOR]

Objectives. We aimed to demonstrate the potential of precision medicine to describe the inflammatory landscape present in children with suspected appendicitis. Our primary objective was to determine levels of seven inflammatory protein mediators previously associated with intra-abdominal inflammation (C-reactive protein—CRP, procalcitonin—PCT, interleukin-6 (IL), IL-8, IL-10, monocyte chemoattractant protein-1—MCP-1, and serum amyloid A—SAA) in a cohort of children with suspected appendicitis. Subsequently, using a multiplex proteomics approach, we examined an expansive array of novel candidate cytokine and chemokines within this population. Methods. We performed a secondary analysis of targeted proteomics data from Alberta Sepsis Network studies. Plasma mediator levels, analyzed by Luminex multiplex assays, were evaluated in children aged 5-17 years with nonappendicitis abdominal pain (NAAP), acute appendicitis (AA), and nonappendicitis sepsis (NAS). We used multivariate regression analysis to evaluate the seven target proteins, followed by decision tree and heat mapping analyses for all proteins evaluated. Results. 185 children were included: 83 with NAAP, 79 AA, and 23 NAS. Plasma levels of IL-6, CRP, MCP-1, PCT, and SAA were significantly different in children with AA compared to those with NAAP (p<0.001). Expansive proteomic analysis demonstrated 6 patterns in inflammatory mediator profiles based on severity of illness. A decision tree incorporating the proteins CRP, ferritin, SAA, regulated on activation normal T-cell expressed and secreted (RANTES), monokine induced by gamma interferon (MIG), and PCT demonstrated excellent specificity (0.920) and negative predictive value (0.882) for children with appendicitis. Conclusions. Multiplex proteomic analyses described the inflammatory landscape of children presenting to the ED with suspected appendicitis. We have demonstrated the feasibility of this approach to identify potential novel candidate cytokines/chemokine patterns associated with a specific illness (appendicitis) amongst those with a broad ED presentation (abdominal pain). This approach can be modelled for future research initiatives in pediatric emergency medicine. [ABSTRACT FROM AUTHOR]

Background: Neuromyelitis optica spectrum disorder (NMOSD) is an anti‐aquaporin 4 (anti‐AQP4) autoantibodies‐mediated idiopathic inflammatory demyelinating disease of the central nervous system. While intravenous pulse methylprednisolone (IVMP) is the recommended initial treatment option for acute onset NMOSD, its therapeutic mechanism remains unclear. We hypothesized that IVMP would reduce the expression of pro‐inflammatory factors and increase the resolution of inflammation in patients with NMOSD. Methods: Mendelian randomization (MR) analysis was used to screen meaningful inflammatory and resolution factors for inclusion. Three MR methods with inverse variance weighting (IVW) were primarily used to identify positive results. Interleukin (IL)‐10, IL‐1β, IL‐6, C‐X‐C motif chemokine ligand 12 (CXCL12), and tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL) were screened from 41 inflammatory factors, and resolvin D1 (RvD1), maresin 1 (MaR1), and lipoxin A4 (LXA4) were screened from 6 resolution markers for inclusion. Subsequently, 12 patients with NMOSD were enrolled and treated with IVMP. Serum levels of the aforementioned inflammatory and resolution markers were measured by enzyme‐linked immunosorbent assay before and after IVMP treatment. Results: High levels of TRAIL, CXCL12, and IL‐1β were associated with an increased risk of NMOSD (TRAIL: odds ratio [OR], 1.582; 95% confidence interval [CI], 1.003–2.495; CXCL12: OR, 3.610; 95% CI, 1.011–12.889; IL‐1β: OR, 4.500; 95% CI, 1.129–17.927). High levels of RvD1, MaR1, and LXA4 were associated with a reduced risk of NMOSD (RvD1: OR, 0.725; 95% CI, 0.538–0.976; MaR1: OR, 0.985; 95% CI, 0.970–0.999; LXA4: OR, 0.849; 95% CI, 0.727–0.993). Among patients with NMOSD, serum levels of IL‐6, CXCL12, and TRAIL significantly decreased following IVMP treatment, compared with pretreatment levels, while levels of IL‐1β, LXA4, and MaR1 significantly increased after IVMP treatment (p < 0.05). A significant positive correlation was observed between CXCL12 levels and Expanded Disability Status Scale (EDSS) scores (r = 0.451, p < 0.05). Conclusion: Several systemic inflammatory regulators associated with the pathogenesis of NMOSD were identified. The protective roles of LXA4 and MaR1 may be indispensable components of glucocorticoid treatment. Therefore, the use of resolution markers may be a potential strategy for improving central nervous system injury in individuals with NMOSD. [ABSTRACT FROM AUTHOR]

Posttransplantation complications pose a major challenge to the long‐term survival and quality of life of organ transplant recipients. These complications encompass immune‐mediated complications, infectious complications, metabolic complications, and malignancies, with each type influenced by various risk factors and pathological mechanisms. The molecular mechanisms underlying posttransplantation complications involve a complex interplay of immunological, metabolic, and oncogenic processes, including innate and adaptive immune activation, immunosuppressant side effects, and viral reactivation. Here, we provide a comprehensive overview of the clinical features, risk factors, and molecular mechanisms of major posttransplantation complications. We systematically summarize the current understanding of the immunological basis of allograft rejection and graft‐versus‐host disease, the metabolic dysregulation associated with immunosuppressive agents, and the role of oncogenic viruses in posttransplantation malignancies. Furthermore, we discuss potential prevention and intervention strategies based on these mechanistic insights, highlighting the importance of optimizing immunosuppressive regimens, enhancing infection prophylaxis, and implementing targeted therapies. We also emphasize the need for future research to develop individualized complication control strategies under the guidance of precision medicine, ultimately improving the prognosis and quality of life of transplant recipients. [ABSTRACT FROM AUTHOR]

Background: T-helper (Th) 2 cytokines are thought to mediate most of the allergic inflammatory responses associated with atopic asthma. But the Th1-related chemokine, interferon-inducible protein 10 (IP-10)/CXCL10, was the predominant chemokine measured during human allergic pulmonary late-phase reaction. The aim of the present study was to evaluate the role of Th1- and Th2- related chemokines in the pathogenesis of asthma exacerbation. Methods: Plasma levels of the Th2-related C-C chemokine I-309 (CCL1), the Th1-related CXC chemokines IP-10, and the monokine induced by interferon-γ (Mig)/CXCL9 were measured in patients with stable asthma. Results: These results were compared to the results measured prior to, and after corticosteroid treatment, in patients who experienced asthma exacerbations. A significant increase in the plasma levels of IP-10 and Mig, but not I-309, were found in patients with an acute exacerbation in contrast to patients with stable asthma. Plasma levels of IP-10 and Mig were significantly higher in patients during an acute asthma exacerbation than during a subsequent convalescent period. Conclusions: The Th1-related CXC chemokines IP-10 and Mig may be useful inflammatory markers of asthma exacerbation in children. [ABSTRACT FROM AUTHOR]

Background: The infiltration of lymphocytes in tumor tissue has been associated with a good prognosis for patients with hepatocellular carcinoma (HCC). The purpose of the present study was to estimate the correlation between mRNA expression of chemokines and tumor-infiltrating lymphocytes in HCC. Methods: A total of 44 HCC were examined. Immunohistochemical staining was performed using antibodies to CD4, CD8, CD68, and L-26. The mRNA expression of each chemokine was investigated: regulated upon activation normal T-cell expressed and secreted (RANTES), interleukin-8 (IL-8), epithelial-derived neutrophil attractant-78 (ENA78), interferon-inducible protein-10 (IP-10), monokine induced by interferon-γ (Mig), and interferon-γ in HCC were quantified via a real-time polymerase chain reaction assay. Chemokine proteins of Mig and IP-10 were examined by immunohistochemistry. Results: The mean number of infiltrating lymphocytes in HCC was 136.9 ± 32.9/0.25 mm2. Of these infiltrating lymphocytes, CD8-positive T lymphocytes were those predominantly seen around the tumor cells. The mean mRNA expression (copies/103 glyceraldehyde-3-phosphate dehydrogenase [GAPDH] mRNA) of the following chemokines was determined to be follows: 3.0 ± 1.9 copies/103 GAPDH mRNA, RANTES; 9.2 ± 4.9 copies/103 GAPDH mRNA, IL-8; 44.6 ± 24.4 copies/103 GAPDH mRNA, ENA78; 215.7 ± 93.9 copies/103 GAPDH mRNA, IP-10; 77.3 ± 38.5 copies/103 GAPDH mRNA, Mig; and 1.7 ± 0.4 copies/103 GAPDH mRNA, interferon-γ. Significant close correlations were observed between the number of infiltrating lymphocytes in these HCC and the expression of Mig and IP-10 mRNA. In the immunostaining, expression of Mig and IP-10 proteins was found only in the HCC cells in the high-infiltration group. Conclusions: Some chemokines induced by interferon-γ, such as Mig and IP-10, may promote lymphocyte recruitment to HCC and may thus play important roles in cancer immunology. [ABSTRACT FROM AUTHOR]

The potential role of chemokines in clinical tumors remains poorly understood. Recent investigations have shown the differential expression of chemokine receptors on lymphocytes mediating Th1- and Th2-type immune responses. We examined Th1- and Th2-associated cytokines and chemokines, as well as the expression of their receptors in tumor-infiltrating lymphocytes in renal cell carcinoma (RCC). Sixty-seven patients with sporadic RCC were analyzed for the expression of Th1- and Th2-associated genes using real-time polymerase chain reaction. Tumor infiltration by CXC chemokine receptor 3 (CXCR3)-positive and CC chemokine receptor 5 (CCR5)-positive cells was detected by immunohistochemistry and by flow cytometry. The expression of Th1-associated genes was significantly increased in tumors compared to normal kidney tissues. The expression of interferon-γ correlated positively with that of Th1 chemokines. Tumors expressing higher Th1 chemokines did not recur after curative surgery. Multivariate analysis showed that increased monokine induced by interferon (IFN)-γ (MIG) expression was an independent favorable prognostic factor. Immunohistochemistry showed that the degree of CXCR3-positive cell infiltration significantly correlated with IFN-γ inducible protein 10, MIG and IFN-γ-inducible T cell a chemoattractant expression (I-TAC). Flow cytometric analysis showed increased expression of CXCR3 and CCR5 in tumor-infiltrating T lymphocytes compared to that in peripheral blood T cells. These results suggest that upregulation of the Th1-type immune response in RCC tumors with a favorable prognosis may be mediated by Th1-associated chemokines. Integrity of the Th1-type immune response seems to be required for tumor regression, suggesting that detection and correction of a defect in the Th1-type response cascade would thus be one of the main targets for tailor-made immunotherapy and gene therapy in RCC. ( Cancer Sci 2006; 97: 780–786) [ABSTRACT FROM AUTHOR]

Hårdstedt M, Finnegan CP, Kirchhof N, Hyland KA, Wijkstrom M, Murtaugh MP, Hering BJ. Post-transplant upregulation of chemokine messenger RNA in non-human primate recipients of intraportal pig islet xenografts.Xenotransplantation 2005; 12: 293–302.© Blackwell Munksgaard, 2005We have previously shown that pig-to-primate intraportal islet xenografts reverse diabetes, escape hyperacute rejection, and undergo acute cellular rejection in non-immunosuppressed recipients. To gain a better understanding of mechanisms contributing to xenoislet rejection in non-human primates we examined gene expression in livers bearing islet xenografts in the first 72 h after transplantation.Liver specimens were collected at sacrifice from seven non-immunosuppressed rhesus macaques at 12, 24, 48 and 72 h after intraportal porcine islet transplantation. Following total RNA extraction, mRNA was quantified using SYBR green real-time reverse transcription polymerase chain reaction (RT-PCR) for species-specific immune response genes. Data were analyzed using comparative cycle threshold (Ct) analysis, adjusted for specific primer-efficiencies and normalized to cyclophilin expression.Porcine insulin mRNA was detected in all liver samples. Cluster analysis revealed differential gene expression patterns at 12 and 24 h (early) compared with at 48 and 72 h (late) post-transplant. Gene expression patterns were associated with histological findings of predominantly neutrophils and only a few lymphocytes at 12 and 24 h and an increasing number of lymphocytes and macrophages at 48 and 72 h. Transcript levels of CXCR3 and its ligands, interferon-inducible protein 10 (IP-10) and monokine induced by IFN-γ (Mig), significantly increased between early and late time points together with expression of MIP-1α, regulated on activation normal T expressed and secreted protein (RANTES) and MCP-1. CCR5 showed only a marginal, non-significant increase. Fas ligand, perforin and granzyme B transcripts were all elevated at 48 and 72 h post-transplant.Our data suggest that CXCR3, with ligands IP-10 and Mig, is involved in T cell recruitment in acute islet xenograft rejection in non-human primates. Upregulation of RANTES and MIP-1α transcripts in the absence of a significant CCR5 increase suggests a possible involvement of other chemokine receptors. MCP-1 expression is associated with T cell and macrophage infiltration. Elevated cytotoxic effector molecule expression (Fas ligand, perforin, granzyme B) indicates T-cell mediated graft destruction by cytotoxic and cytolytic mechanisms within 48 to 72 h after transplantation. These results identify the CXCR3-mediated chemoattractant pathway as an immunosuppressive target in pig-to-primate islet xenotransplantation. [ABSTRACT FROM AUTHOR]

CXCR3 chemokines are of particular interest because of their potential involvement in a variety of inflammatory diseases, including the rejection of organ transplants. Although the rat is one of the most appropriate animals for using to study transplantation biology, the structural and functional characteristics of CXCL9 [monokine induced by interferon-γ (Mig)] in this experimental model have not been described. Therefore, we recently conducted a series of experiments to identify and characterize the rat CXCL9 gene. Accordingly, we isolated rat CXCL9 cDNA and genomic DNA. The rat CXCL9 gene encodes a protein of 125 amino acids and spans a 3·5 kbp DNA segment containing four exons in the protein-coding region. We then analysed mRNA expression in various tissues. Transcripts for the gene were found to be expressed at high levels in the lymph nodes and spleen. Then, to confirm the function of the identified gene, rat CXCL9 was transiently expressed in COS-1 cells. Rat recombinant Mig displayed chemotactic properties and induced CXCR3 internalization in CD4+ T cells. Lastly, we analysed the expression of rat CXCL9 in a heterotopic heart allograft model. Both mRNA and protein levels of intragraft CXCL9 were significantly increased following transplantation of ACI to LEW hearts when compared with syngeneic controls. These findings indicate that rat CXCL9 has an in vivo role in the infiltration of CD4+ T cells in the transplanted graft. [ABSTRACT FROM AUTHOR]