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Background: It has been suggested that increased monocyte responses might play a role in chronic allograft rejection., Methods: We investigated in vitro monokine responses in 112 patients with long-term stable kidney graft function (ST patients; n=80, non-mycophenolate mofetil [MMF]; n=32, MMF) and 25 patients with chronic renal transplant rejection (CR patients; non-MMF). Interleukin 10 and tumor necrosis factor (TNF)-alpha promoter gene polymorphisms were tested by polymerase chain reaction and sequence-specific primers; antigen-presenting capacity (AC) of monocytes was tested by incubation with staphylococcal superantigens (SEA, SEE, SED)., Results: Although non-MMF-based immunosuppression in ST patients did not result in compromised AC or lipopolysaccharide (LPS)-stimulated monokine responses compared with healthy controls, we found MMF therapy to be associated with significantly reduced TNF-R1 expression on monocytes (P<0.001), suppressed AC (P<0.02, SED), and suppressed LPS-stimulated IL-1 beta, IL-10, and TNF-alpha secretion (P<0.01). Coinciding with a significantly higher steroid dosage in CR patients, IL-6 receptor and TNF-R1 expression on monocytes were down-regulated (P< or =0.02) and AC was suppressed in CR compared with ST (non-MMF) patients (P<0.01, SED; P<0.05, SEE). However, LPS-stimulated monokine secretion was not decreased or even enhanced (IL-6, granulocyte-macrophage colony-stimulating factor [GM-CSF]; P<0.05). Enhanced in vitro IL-10 responses (>500 pg/mL) were found predominantly in non-MMF-treated patients with the IL-10 genotype GCC (GCC: 23/62 [37%], non-GCC: 2/27 [7%], P<0.005; GCC and non-MMF: 22/47 [47%], GCC and MMF: 1/15 [7%], P<0.005]., Conclusion: Steroids and azathioprine did not sufficiently suppress monokine responses, whereas MMF treatment might inhibit chronic graft rejection because of suppression of TNF-R1 expression and vigorous inhibition of monokine secretion. MMF treatment may especially be indicated in patients with the IL-10 "high-producer" genotype GCC.

Whole-cell pertussis found in diphtheria-tetanus-pertussis (DTP) vaccine can produce symptoms reminiscent of biological responses to circulating proinflammatory monokines such as IL-6, IL-1beta, and TNFalpha. Therefore the ability of pertussis-containing vaccines and several heat-killed Bordetella pertussis preparations to stimulate cytokine production in a human monocytic cell line, THP-1, were examined. The whole-cell pertussis vaccine induced significantly more IL-6, IL-1beta, and TNFalpha production than did the acellular pertussis or diphtheria-tetanus-only vaccine. Polymyxin B was able to inhibit most of the IL-6 induced by pertussis endotoxin and a heat-killed preparation of B. pertussis containing a null mutation in bvgAS, a regulatory locus required for expression of all known protein virulence factors synthesized by this organism. However, it only partially inhibited IL-6 production induced by other pertussis-containing preparations, including DTP vaccine. These results indicate that in vitro whole-cell vaccine is a potent stimulator of IL-6, IL-1beta, and TNFalpha. They also suggest that although endotoxin is a major inducer of IL-6, other components of B. pertussis also contribute to IL-6 production by monocytes.

Langerhans' cell histiocytosis (LCH) is a clonal proliferation of Langerhans cells (LC) showing histologically an abundant reactive infiltrate composed of macrophages and lymphocytes, as well as eosinophilic and neutrophilic granulocytes. Rosai-Dorfman disease (RDD) shows a sinusoidal accumulation of large histiocytic cells with an immunophenotype similar to LC of LCH. The histological picture of LCH is reminiscent of an inflammatory disorder and LC may produce cytokines and are influenced by these soluble factors. This study set out to establish the monokine expression pattern in LCH in comparison with those of RDD; dermatopathic lymphadenopathy, which also shows a proliferation of S100-positive dendritic cells; and LC in normal skin specimens. Isotopic in situ hybridization was used for the detection of transcripts of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1 beta, in some cases combined with immunohistology for the S100 protein or CD68. In all 11 tissue samples from eight patients, LC of LCH expressed TNF-alpha; in two cases IL-1 beta transcripts were additionally noted in some LC, whereas IL-6 was found in reactive cells. Large histiocytic cells of RDD expressed all three monokines, whereas minimal or no expression of these cytokines could be detected in interdigitating reticulum cells in dermatopathic lymphadenopathy. In two out of five normal skin samples, only TNF-alpha specific signals were observed in LC. These data suggest that histologically different lesions of the histiocytic/dendritic cell system display distinct cytokine profiles. The expression of monokines, which have been demonstrated to influence various functions of epidermal LC, may play a role in the pathogenesis of LCH. Systemic symptoms in RDD may be related to enhanced production of monokines in these lesions.

As shown previously, thioglycollate-induced peritoneal macrophages consist of two subpopulations which differ morphologically and functionally. When tagged with trinitrophenyl hapten (TNP), one macrophage subpopulation induced in vivo effector cells (Th1) of contact sensitivity (CS) reaction, while the other induced suppressor T cells (Ts) which inhibit CS and are highly sensitive to the in vivo action of cyclophosphamide (CY). Our present experiments show that CY-resistant (Th inducers) and CY-sensitive macrophages (Ts inducers) differ also in the spectrum of biologically relevant molecules which they secrete when stimulated by LPS. Thus macrophages which preferentially induce Th1 cells have a cytokine pattern IL-1LOW, IL-6HIGH, TNF-alpha LOW, while macrophages which recruit Ts cells are IL-1HIGH, IL-6LOW, TNF-alpha HIGH. TH1 inducers produced also somewhat better PGE2 then Ts inducers. Production of reactive nitrogen intermediates (NO/NO2-) was similar in both groups of macrophages. The reasons for the differential effect of CY on these two populations is not clear at present, although it is known that CY metabolites can bind to sulfhydryl groups on antigen presenting cells (APC) and thereby up- or downregulate the antigen presenting capacities of separate subpopulations of APC.

To examine the regulation of cytokine synthesis during murine listeriosis, we have monitored IFN-gamma, TNF-alpha, and IL-1 beta mRNA levels in the spleens of C57B1/6 mice after the i.v. infusion of virulent and nonvirulent preparations of Listeria monocytogenes (LM). Messenger RNA coding for TNF, IL-1, or IFN did not become detectable until approximately 12 to 15 h after the infusion of virulent LM. Levels of each cytokine mRNA then increased synchronously reaching peak or near peak levels around 24 h after infection. Levels gradually decreased over the next 4 to 5 days. Unlike virulent LM, neither heat-killed LM, nor nonvirulent LM variants lacking listeriolysin O, stimulated monokine or IFN mRNA accumulation even when administered in very large doses. To gain perspective concerning the response to LM, we examined the early pattern of cytokine mRNA accumulation induced by Salmonella typhimurium (ST), an intracellular pathogen expressing LPS. We noted at least three significant differences between the cytokine responses to LM and ST: 1) monokine mRNA levels increased much more rapidly (within 1 h) after ST infection; 2) unlike LM, ST retained the capacity to stimulate cytokine mRNA production when injected as heat-killed bacteria; 3) in contrast to LM, ST could not trigger the early IFN production characteristic of LM infection. Our data suggest that monokine and IFN production early in listeriosis are critically linked with the process of bacterial invasion of host cells. The timing and pattern of cytokine mRNA accumulation in this setting is qualitatively different from that induced by LPS. The pathway described in these studies may also play a role in the host cytokine response to other intracellular pathogens as well.

As the eponymous mediators of the cytokine storm syndrome, cytokines are a pleomorphic and diverse set of soluble molecules that activate or suppress immune functions in a wide variety of ways. The relevant cytokines for each CSS are likely a result of differing combinations of environmental triggers and host susceptibilities. Because cytokines or their receptors may be specifically targeted by biologic therapeutics, understanding which cytokines are relevant for disease initiation and propagation for each unique CSS is of major clinical importance. This chapter will review what is known about the role of cytokines across the spectrum of CSS., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Diffuse large B cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma. Studies indicated that inflammatory cytokines involved in the occurrence and progression of DLBCL and it is challenging to discern causality from the effects due to the presence of feedback loops. We conducted a bidirectional Mendelian randomization (MR) study to investigate the potential causal relationship between DLBCL and inflammatory cytokines. The genetic variants associated with inflammatory cytokines were obtained from a genome-wide association study (GWAS) involving 8293 European participants, and the data on 1010 individuals with DLBCL were sourced from the FinnGen consortium. The primary method employed in this study was the inverse-variance weighted (IVW) method, with supplementary analyses conducted using the MR-Egger, weighted median, and MR-PRESSO approaches. Based on the IVW method, genetically predicted that increasing level of Monokine induced by interferon gamma (MIG/CXC chemokine ligand 9, CXCL9) [OR: 1.31; 95% CI: 1.05-1.62; P = 0.01] and interferon gamma-induced protein 10(IP-10/CXC chemokine ligand 10, CXCL10) [OR: 1.30; 95% CI: 1.02-1.66; P = 0.03] showed suggestive associations with DLBCL risk. DLBCL may increase the level of macrophage colony-stimulating factor (M-CSF) [OR: 1.12; 95% CI: 1.01-1.2; P = 0.03], tumor necrosis factor beta (TNF-β) [OR: 1.16; 95% CI: 1.02-1.31; P = 0.02] and TNF-related apoptosis-inducing ligand (TRAIL) [OR: 1.07; 95% CI: 1.01-1.13; P = 0.02]. This study presents evidence supporting a causal relationship between inflammation cytokines and DLBCL. Specifically, MIG/CXCL9 and IP-10/CXCL10 were identified as indicators of upstream causes of DLBCL; while, DLBCL itself was found to elevate the levels of M-CSF, TNF-β, and TRAIL. These findings suggest that targeting specific inflammatory factors through regulation and intervention could serve as a potential approach for the treatment and prevention of DLBCL., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Interactions between cytokines play an important role in the development of thyroid autoimmunity. Using enzyme-linked immunosorbent assay we investigated serum concentrations of soluble interleukin-2 receptor (sIL-2R), interferon-gamma, tumour necrosis factor (TNF)-α, interleukin (IL)-10, CD30, monokine induced by interferon-gamma (MIG), cytotoxic T lymphocyte antigen-4 and markers of apoptosis decoy receptor 3 and Bcl-2 in 28 patients with hyperthyroid Graves' disease (GD), 24 patients with untreated Hashimoto's thyroiditis (HT) and 15 healthy controls. TNF-α, IL-10 and sIL-2R were higher in GD compared with HT and controls (TNF-α: 8·79 in GD versus 2·54 pg/ml in HT, P = 0·01; IL-10: 10·00 versus 3·10 versus 3·10 pg/ml, P1 < 0·001, P2 = 0·005; sIL-2R: 1·26 versus 0·64 versus 0·46 ng/ml, P < 0·001). MIG and CD30 were higher in HT compared with controls (649·22 ± 262·55 versus 312·95 ± 143·35 pg/ml, P = 0·037, 6·57 ± 2·35 versus 3·03 ± 1·04 U/ml, P = 0·036 respectively). In GD sIL-2R decreased when the euthyroid state was achieved (1·31 ± 0·64 versus 0·260 ± 0·11, n = 12, P < 0·001). sIL-2R correlated positively with free thyroxine (FT4) ( R = 0·521, P = 0·000) and negatively with thyroid stimulating hormone (TSH) ( R = −0·472, P = 0·00132). MIG correlated negatively with FT4 ( R = −0·573, P = 0·00234) and positively with TSH (R = 0·462, P = 0·0179). The results suggest that serum concentrations of sIL-2R and MIG are related to thyroid function rather than to activation of autoimmunity. [ABSTRACT FROM AUTHOR]

Sydenham''s chorea (SC) is thought to result from the action of streptococcus-induced antibodies that cross react with basal ganglia antigens. Much less is known, however, about the involvement of cellular mechanisms in its pathogenesis. Since chemokines seem to play a role in several CNS inflammatory disorders, we sought to investigate the chemokine profile of patients with SC. Increased serum levels of CXCL9, formerly monokine induced by interferon-γ (Mig), and CXCL10, formerly interferon-γ-inducible protein of 10 kDa (IP-10) were demonstrated in acute SC patients, suggesting that a particular group of chemokines may be involved in SC pathogenesis. [Copyright &y& Elsevier]

Purpose of Review: Chimeric antigen receptor (CAR)-T-cell therapy is a revolutionary tool in the treatment of cancer. CAR-T cells exhibit their effector functions through the recognition of their specific antigens on tumor cells and recruitment of other immune cells. However, this therapy is limited by the development of severe toxicities and modest antitumor activity in solid tumors. The host and tumor microenvironment interactions with CAR-T cells play an important role in orchestrating CAR-T-cell functions. Specifically, myeloid lineage cells and their cytokines critically influence the behavior of CAR-T cells. Here, we review the specific effects of myeloid cell interactions with CAR-T cells, their impact on CAR-T-cell response and toxicities, and potential efforts to modulate myeloid cell effects to enhance CAR-T-cell therapy efficacy and reduce toxicities., Recent Findings: Independent studies and correlative science from clinical trials indicate that inhibitory myeloid cells and cytokines contribute to the development of CAR-T-cell-associated toxicities and impairment of their effector functions., Summary: These findings illuminate a novel way to reduce CAR-T-cell-associated toxicities and enhance their efficacy through the modulation of myeloid lineage cells and inhibitory cytokines.

Background: As the widely used biomarker of whole-blood stimulation assays for tuberculosis diagnosis, the release of IFN-γ might be affected by multiple factors, such as immunosuppression and some infectious agents. Here, we evaluated additional cytokines as diagnostic biomarkers., Methods: Forty-three cytokines were measured by Luminex xMAP technologies in 30 healthy and 10 naturally Mycobacterium tuberculosis (MTB)-infected rhesus monkeys pre- and post-stimulation by purified protein derivative (PPD)., Results: After stimulation, production of 23 and 38 cytokines was markedly increased in healthy and MTB-infected macaques, respectively. A comparison of the stimulation index (SI) between MTB infections and healthy macaques showed that the SIs of 32 cytokines in MTB-infected macaques were significantly higher than those in healthy macaques. Pooling the results, eight cytokines were suggested as ideal biomarkers for a whole-blood stimulation assay for MTB diagnosis., Conclusion: PPD could induce multiple cytokine responses in either healthy or MTB-infected monkeys, and eight cytokines had reliable predictive capacity as diagnostic biomarkers of MTB infection., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The complex interaction between HIV-1 infection and Mycobacterium avium was studied. Viral burden was assessed, as well as immune response to HIV-1 in the context of Myco, avium infections. We also examined serum cytokine levels and cytokine release by blood niononuclear cells in HIV-1-infected subjects, infected or not with Myco, avium. Undetectable serum levels of IL-I, tumour necrosis factor-alpha (TNE-β and IL-6 were found in normal controls and in groups I, II and IJI of HIV-1-infected subjects. Moderate levels of TNF-α, IL-1 and IL-6 were found in the sera of group IV patients. When group IV was subdivided into subjects with and without Myco. avium infections, subjects with Myco, avium infections were shown to have higher serum levels of TNF-α, IL-1&beta and IL-6 than those with other infections. Blood mononuclear cells from controls and HIV subjects were stimulated with bacterial lipopolysaccharide, and cytokine levels assessed. Cells from group II patients were shown to secrete normal levels of TNF-α and IL-6, and lower levels of lL-β group III subjects released higher levels of IL-6, Patients in group IV had blood cells that released elevated levelsof lL-6 and TNF-α, and lower levels of IL-1β. Group IV subjects with Myco, avium Infections had blood cells that released higher levels of TNF-α, IL-6 and IL-1 than group IV subjects with other infections. Assessment of viral burden in cells of HIV-i-infected subjects revealed that Myco.avium -Infected subjects had a higher level of virus burden and a lower level of lymphoproliferative response to an inactivated gp120-depleted HIV-1 antigen than AIDS subjects with other infections. These data suggest that Myco. avium infections in HIV-1-infected subjects hasten the progression of viral disease, enhance cytokine release and contribute to the anergy to viral antigens. [ABSTRACT FROM AUTHOR]

Background: Based on previous research, it is well-established that myasthenia gravis (MG) is linked to chronic inflammation. However, the exact nature of the relationship between inflammatory factors and the development of MG remains unclear. Consequently, the objective of this study is to explore whether alterations in the levels of inflammatory factors, as influenced by genetic factors, are associated with the occurrence of MG. This will be achieved through a two-sample Mendelian randomization (MR) analysis., Methods: We conducted a bidirectional Mendelian randomization (MR) study utilizing genetic data from genome-wide association studies (GWAS), encompassing 1873 MG cases and 36,370 individuals of European ancestry as controls. Data on inflammatory cytokines were obtained from GWAS data of 8293, healthy participants. The inverse variance-weighted (IVW) method was primarily employed to investigate the causal relationship between exposure and outcome. Additionally, various sensitivity analysis methods such as MR-Egger, weighted median, simple mode, weighted mode, and MR-PRESSO were applied to strengthen the reliability of the results. Through these rigorous approaches, we extensively examined the relationship between inflammatory factors and MG; however, further research is required to establish the specific causal relationship., Results: After applying Bonferroni correction, the genetic predictions revealed a significant correlation between Monokine induced by gamma interferon (MIG) and MG (OR: 1.09, 95 % CI: 1.04-1.14; P = 0.0006). Furthermore, there were preliminary findings indicating a positive genetic association between Eotaxin and interleukin-2 receptor antagonist (IL-2ra) with MG (OR: 0.81, 95 % CI: 0.66-0.99, P = 0.044; OR: 0.80, 95 % CI: 0.68-0.94, P = 0.008). Reverse MR analysis provided initial evidence of associations between MIP1α, GROa, IL-13, TRAIL, IL-2ra, and IL-1ra with the development of MG. No indications of pleiotropy or heterogeneity among genetic variants were observed (P > 0.05)., Conclusion: This study uncovers a new connection between inflammatory cytokines and MG, shedding light on potential factors contributing to the development of the disease. Elevated levels of Eotaxin and IL-2ra are associated with a higher risk of MG, while indicating that MIG, MIP1α, GROa, IL-13, TRAIL, IL-2ra, and IL-1ra may be elevated as a result of MG, Especially MIG. These findings suggest that targeting and regulating specific inflammatory factors could offer promising avenues for the treatment and prevention of MG., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Previous observational studies have reported that systemic cytokines are associated with the risk of inflammatory skin diseases, but their conclusions remain controversial., Method: We conducted a two-sample Mendelian randomization analysis to assess the relationship between systemic cytokines and six inflammatory skin disorders (including alopecia areata (AA), acne, atopic dermatitis (AD), hidradenitis suppurativa (HS), psoriasis (PS) and vitiligo), based on datasets from EArly Genetics and Lifecourse Epidemiology (EAGLE) eczema consortium, acne GWAS conducted by Maris Teder Laving et al., IEU Open GWAS, and FinnGen database. Inverse-variance weighted (IVW) method was conducted in primary MR analysis, and supplemented by MR-Egger, weighted median, weighted mode, and MR-PRESSO., Results: By integrating the findings from both primary and sensitivity analyses, we identified ten systemic cytokines linked to the risk of six skin diseases using the IVW method. Briefly, four cytokines increased the risk of corresponding skin diseases: β-nerve growth factor (β-NGF) to AA (p = 0.005) and HS (p = 0.001), interleukin-8 (p = 0.014) to acne; interleukin-5 (p = 0.042) to AD; interleukin-13 (p = 0.049) to PS. In the meantime, seven cytokines could have protective effect on specific skin diseases: interleukin-9 (p = 0.040) and interleukin-2 receptor subunit alpha (IL-2ra) (p = 0.020) on AA; macrophage inflammatory protein (MIP)-1β (p = 0.020) on acne; monokine induced by IFN-γ (p = 0.006) on AD; interleukin-16 (p = 0.038), MIP-1β (p = 0.017) and IL-2ra (p = 0.020) on PS., Conclusions: This study reveals 13 causal associations between systemic cytokines and 6 skin diseases, offering new perspectives on the prevention and management of widespread inflammatory skin disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objectives: The diagnostic gaps for childhood tuberculosis (TB) remain considerable in settings with high TB incidence and resource constraints. We established and evaluated the performance of a scoring system based on a combination of serological tests and T-cell cytokine release assays, chosen for their ability to detect immune responses indicative of TB, in a context of high prevalence of pediatric HIV infection., Methods: We enrolled 628 consecutive children aged ≤15 years, admitted for TB suspicion. Multiple cytokine levels in QuantiFERON Gold In-Tube supernatants and antigen 85B (Ag85B) antibodies were assessed in children who tested positive with either Xpert TB or mycobacterial culture. The results were compared with those of control children., Results: Among the biomarkers most strongly associated with TB, random forest classification analysis selected Ag85B antibodies, interleukin-2/interferon-γ ratio, and monokine induced by interferon-γ for the scoring system. The receiver operating characteristic curve derived from our scoring system showed an area under the curve of 0.95 (0.91-0.99), yielding 91% sensitivity and 88% specificity. The internal bootstrap validation gave the following 95% confidence intervals for the score performance: sensitivity 71%-97% and specificity 79%-99%., Conclusions: This study suggests that supplementing the QuantiFERON assay with a combination of serological and T-cell markers could enhance childhood TB screening regardless of HIV status and age. Further validation among the target population is necessary to confirm the performance of this scoring system., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Because they are difficult to treat, animal models of widespread, established metastatic cancer are rarely used to test novel immunotherapies. Two such mouse models are used in this report to demonstrate the therapeutic efficacy and to probe the mechanisms of a novel combination immunotherapy consisting of the cytokine interleukin-12 (IL-12) combined with a previously described vaccine based on MHC class II, CD80-expressing cells. BALB/c mice with 3-week established primary 4T1 mammary carcinomas up to 6 mm in diameter and with extensive, spontaneous lung metastases show a significant reduction in lung metastases following a 3-week course of immunotherapy consisting of weekly injections of the cell-based vaccine plus injections of IL-12 three times per week. C57BL/6 mice with 7-day established intravenous B16 melF10 lung metastases show a similar response following immunotherapy with IL-12 plus a vaccine based on B16 MHC class II, CD80-expressing cells. In both systems the combination therapy of cells plus IL-12 is more effective than IL-12 or the cellular vaccine alone, although, in the 4T1 system, optimal activity does not require MHC class II and CD80 expression in the vaccine cells. The cell-based vaccines were originally designed to activate tumor-specific CD4+ T lymphocytes specifically and thereby provide helper activity to tumor-cytotoxic CD8+ T cells, and IL-12 was added to the therapy to facilitate T helper type 1 lymphocyte (Th1) differentiation. In vivo depletion experiments for CD4+ and CD8+ T cells and natural killer (NK) cells and tumor challenge experiments in beige/nude/XID immunodeficient mice demonstrate that the therapeutic effect is not exclusively dependent on a single cell population, suggesting that T and NK cells are acting together to optimize the response. IL-12 may also be enhancing the immunotherapy via induction of the chemokine Mig (monokine induced by interferon γ), because reverse PCR experiments demonstrate that Mig is present in the lungs of mice receiving therapy and is most likely synthesized by the tumor cells. These results demonstrate that the combination therapy of systemic IL-12 and a cell-based vaccine is an effective agent for the treatment of advanced, disseminated metastatic cancers in experimental mouse models and that multiple effector cell populations and anti-angiostatic factors are likely to mediate the effect. [ABSTRACT FROM AUTHOR]

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]

Background: Previous observational studies have suggested the association between rheumatoid arthritis (RA) and frailty. However, it remains obscure whether this association is causal. This study aims to investigate the causal association of RA with frailty and the mediation effect of inflammatory cytokines using Mendelian randomization (MR) design., Methods: Summary-level data for RA (N = 58,284), frailty index (FI) (N = 175,226), Fried frailty score (FFS) (N = 386,565), and 41 inflammatory cytokines (N = 8,293) were obtained from recent genome-wide association studies. Univariable and multivariable MR analyses were conducted to investigate and verify the causal association of RA with frailty. The potential mediation effects of inflammatory cytokines were estimated using two-step MR., Results: Univariable inverse variance weighted MR analysis suggested that genetically determined RA was associated with increased FI (beta=0.021; 95 % CI: 0.012, 0.03; p = 2.2 × 10 -6 ) and FFS (beta=0.011; 95 %CI: 0.007, 0.015; p = 8.811 × 10 -8 ). The consistent results were observed in multivariable MR analysis after adjustment for asthma, smoking, BMI, physical activity, telomere length, and depression. Mediation analysis showed evidence of an indirect effect of RA on FI through monokine induced by interferon-gamma (MIG) with a mediated proportion of 9.8 % (95 %CI: 4.76 %, 19.05 %), on FFS via MIG and stromal cell-derived factor-1 alpha with a mediated proportion of 9.6 % (95 %CI: 0 %, 18.18 %) and 8.44 % (95 %CI: 0 %, 18.18 %), respectively., Conclusion: This study provided credible evidence that genetically predicted RA was associated with a higher risk of frailty. Additionally, inflammatory cytokines were involved in the mechanism of RA-induced frailty., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier B.V.)

Background: Human adipose-derived stromal/stem cells (hASCs) play important roles in regenerative medicine and numerous inflammatory diseases. However, their cellular heterogeneity limits the effectiveness of treatment. Understanding the distinct subtypes of hASCs and their phenotypic implications will enable the selection of appropriate subpopulations for targeted approaches in regenerative medicine or inflammatory diseases. Methods: hASC subtypes expressing dipeptidyl peptidase-4 (DPP4) were identified via fluorescence-activated cell sorting (FACS) analysis. DPP4 expression was knocked down in DPP4+ hASCs via DPP4 siRNA. The capacity for proliferation, hepatocyte differentiation, inflammatory factor secretion and T-cell functionality regulation of hASCs from DPP4−, DPP4+, and control siRNA-treated DPP4+ hASCs and DPP4 siRNA-treated DPP4+ hASCs were assessed. Results: DPP4+ hASCs and control siRNA-treated DPP4+ hASCs presented a lower proliferative capacity but greater hepatocyte differentiation capacity than DPP4− hASCs and DPP4 siRNA-treated DPP4+ hASCs. Both DPP4+ hASCs and DPP4− hASCs secreted high levels of vascular endothelial growth factor-A (VEGF-A), monocyte chemoattractant protein-1 (MCP-1), and interleukin 6 (IL-6), whereas the levels of other factors, including matrix metalloproteinase (MMP)-1, eotaxin-3, fractalkine (FKN, CX3CL1), growth-related oncogene-alpha (GRO-alpha, CXCL1), monokine induced by interferon-gamma (MIG), macrophage inflammatory protein (MIP)-1beta, and macrophage colony-stimulating factor (M-CSF), were significantly greater in the supernatants of DPP4+ hASCs than in those of DPP4− hASCs. Exposure to hASC subtypes and their conditioned media triggered changes in the secreted cytokine profiles of T cells from healthy donors. The percentage of functional T cells that secreted factors such as MIP-1beta and IL-8 increased when these cells were cocultured with DPP4+ hASCs. The percentage of polyfunctional CD8+ T cells that secreted multiple factors, such as IL-17A, tumour necrosis factor alpha (TNF-α) and TNF-β, decreased when these cells were cocultured with supernatants derived from DPP4+ hASCs. Conclusions: DPP4 may regulate proliferation, hepatocyte differentiation, inflammatory cytokine secretion and T-cell functionality of hASCs. These data provide a key foundation for understanding the important role of hASC subpopulations in the regulation of T cells, which may be helpful for future immune activation studies and allow them to be customized for clinical application. [ABSTRACT FROM AUTHOR]

Abstract: Causal relationships between gut microbiota, inflammatory cytokines, and diffuse large B-cell lymphoma (DLBCL) remain elusive. In addressing this gap, our Mendelian randomization (MR) study used data from the MiBioGen consortium encompassing 211 microbiota taxa (n = 18 340), genome-wide association study meta-analyses of 47 inflammatory cytokines, and DLBCL cases and controls from the FinnGen consortium (cases, n = 1010; controls, n = 287 137). Through bidirectional MR analyses, we examined the causal links between gut microbiota and DLBCL and used mediation analyses, including 2-step MR and multivariable MR (MVMR), to identify potential mediating inflammatory cytokines. Our findings revealed that 4 microbiota taxa were causally associated with DLBCL, and conversely, DLBCL influenced the abundance of 20 taxa. Specifically, in the 2-step MR analysis, both the genus Ruminococcaceae UCG-002 (odds ratio [OR], 1.427; 95% confidence interval [CI], 1.011-2.015; P = .043) and the inflammatory cytokine monokine induced by gamma (MIG) (OR, 1.244; 95% CI, 1.034-1.487; P = .020) were found to be causally associated with an increased risk of DLBCL. Additionally, a positive association was observed between genus Ruminococcaceae UCG-002 and MIG (OR, 1.275; 95% CI, 1.069-1.520; P = .007). Furthermore, MVMR analysis indicated that the association between genus Ruminococcaceae UCG-002 and DLBCL was mediated by MIG, contributing to 14.9% of the effect (P = .005). In conclusion, our MR study provides evidence that supports the causal relationship between genus Ruminococcaceae UCG-002 and DLBCL, with a potential mediating role played by the inflammatory cytokine MIG., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objective: To investigate profiles of circulating immune signatures in healthy controls and chronic pancreatitis patients (CP) with and without a preceding history of acute pancreatitis (AP)., Methods: We performed a phase 1, cross-sectional analysis of prospectively collected serum samples from the PROspective Evaluation of Chronic Pancreatitis for EpidEmiologic and Translation StuDies (PROCEED) study. All samples were collected during a clinically quiescent phase. CP subjects were categorized into two subgroups based on preceding episode(s) of AP. Healthy controls were included for comparison. Blinded samples were analyzed using an 80-plex Luminex assay of cytokines, chemokines, and adhesion molecules. Group and pairwise comparisons of analytes were performed between the subgroups., Results: In total, 133 patients with CP (111 with AP and 22 without AP) and 50 healthy controls were included. Among the 80 analytes studied, CP patients with a history of AP had significantly higher serum levels of pro-inflammatory cytokines (interleukin (IL)-6, IL-8, IL-1 receptor antagonist, IL-15) and chemokines (Cutaneous T-Cell Attracting Chemokine (CTACK), Monokine induced Gamma Interferon (MIG), Macrophage-derived Chemokine (MDC), Monocyte Chemoattractant Protein-1 (MCP-1)) compared to CP without preceding AP and controls. In contrast, CP patients without AP had immune profiles characterized by low systemic inflammation and downregulation of anti-inflammatory mediators, including IL-10., Conclusion: CP patients with a preceding history of AP have signs of systemic inflammatory activity even during a clinically quiescent phase. In contrast, CP patients without a history of AP have low systemic inflammatory activity. These findings suggest the presence of two immunologically diverse subtypes of CP., (Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Objective: In the pathogenesis of myeloproliferative neoplasms (MPN), inflammation plays an important role. However, it is unclear whether there is a causal link between inflammation and MPNs. We used a bidirectional, two-sample Mendelian randomization (MR) approach to investigate the causal relationship between systemic inflammatory cytokines and myeloproliferative neoplasms., Methods: A genome-wide association study (GWAS) of 8293 European participants identified genetic instrumental variables for circulating cytokines and growth factors. Summary statistics of MPN were obtained from a GWAS including 1086 cases and 407,155 controls of European ancestry. The inverse-variance-weighted method was mainly used to compute odds ratios (OR) and 95% confidence intervals (Cl)., Results: Our results showed that higher Interleukin-2 receptor, alpha subunit (IL-2rα) levels, and higher Interferon gamma-induced protein 10 (IP-10) levels were associated with an increased risk of MPN (OR = 1.36,95%CI = 1.03-1.81, P = 0.032; OR = 1.55,95%CI = 1.09-2.22, P = 0.015; respectively).In addition, Genetically predicted MPN promotes expression of the inflammatory cytokines interleukin-10 (IL-10) (BETA = 0.033, 95% CI = 0.003 ~ 0.064, P = 0.032) and monokine induced by interferon-gamma (MIG) (BETA = 0.052, 95% CI = 0.002-0.102, P = 0.043) and, on activation, normal T cells express and secrete RANTES (BETA = 0.055, 95% CI = 0.0090.1, P = 0.018)., Conclusion: Our findings suggest that cytokines are essential to the pathophysiology of MPN. More research is required if these biomarkers can be used to prevent and treat MPN., (© 2024. The Author(s).)

Background: Autoimmune thyroid disease (AITD) ranks among the most prevalent thyroid diseases, with inflammatory cytokines playing a decisive role in its pathophysiological process. However, the causal relationship between the inflammatory cytokines and AITD remains elusive., Methods: A two-sample Mendelian randomization (MR) analysis was performed to elucidate the causal connection between AITD and 41 inflammatory cytokines. Genetic variations associated with inflammatory cytokines were sourced from the FinnGen biobank, whereas a comprehensive meta-analysis of genome-wide association studies (GWASs) yielded data on Graves' disease (GD) and Hashimoto thyroiditis. Regarding the MR analysis, the inverse variance-weighted, MR-Egger, and weighted median methods were utilized. Additionally, sensitivity analysis was conducted using MR-Egger regression, MR-pleiotropy residual sum, and outliers., Results: Seven causal associations were identified between inflammatory cytokines and AITD. High levels of tumor necrosis factor-β and low levels of stem cell growth factor-β were indicative of a higher risk of GD. In contrast, high levels of interleukin-12p70 (IL-12p70), IL-13, and interferon-γ and low levels of monocyte chemotactic protein-1 (MCP-1) and TNF-α suggested a higher risk of HD. Moreover, 14 causal associations were detected between AITD and inflammatory cytokines. GD increases the levels of macrophage inflammatory protein-1β, MCP-1, monokine induced by interferon-γ (MIG), interferon γ-induced protein 10 (IP-10), stromal cell-derived factor-1α, platelet-derived growth factor BB, β-nerve growth factor, IL-2ra, IL-4, and IL-17 in blood, whereas HD increases the levels of MIG, IL-2ra, IP-10, and IL-16 levels., Conclusion: Our bidirectional MR analysis revealed a causal relationship between inflammatory cytokines and AITD. These findings offer valuable insights into the pathophysiological mechanisms underlying AITD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yao, Guo, Tan, Zhang, Geng, Yang and Wang.)

Objective: Investigating the association between inflammatory cytokines and hypothyroidism remains challenging due to limitations in traditional observational studies. In this study, we employed Mendelian randomization (MR) to assess the causal relationship between 41 inflammatory cytokines and hypothyroidism., Method: Inflammatory cytokines in 30,155 individuals of European ancestry with hypothyroidism and in a GWAS summary containing 8,293 healthy participants were included in the study for bidirectional two-sample MR analysis. We utilized inverse variance weighting (IVW), weighted median (WM), and Mendelian randomization-Egger (MR-Egger) methods. Multiple sensitivity analyses, including MR-Egger intercept test, leave-one-out analysis, funnel plot, scatterplot, and MR-PRESSO, were applied to evaluate assumptions., Results: We found evidence of a causal effect of IL-7 and macrophage inflammatory protein-1β (MIP-1β) on the risk of hypothyroidism, and a causal effect of hypothyroidism on several cytokines, including granulocyte colony-stimulating factor (G-CSF), IL-13, IL-16, IL-2rα, IL-6, IL-7, IL-9, interferon-γ-inducible protein 10 (IP10), monokine induced by interferon (IFN)-γ (MIG), macrophage inflammatory protein-1β (MIP-1β), stem cell growth factors-β (SCGF-β), stromal cell derived factor-1α (SDF-1α), and tumor necrosis factor-α (TNF-α)., Conclusion: Our study suggests that IL-7 and MIP-1β may play a role in the pathogenesis of hypothyroidism, and that hypothyroidism may induce a systemic inflammatory response involving multiple cytokines. These findings may have implications for the prevention and treatment of hypothyroidism and its complications. However, further experimental studies are needed to validate the causal relationships and the potential of these cytokines as drug targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lai, Yin, Feng, Deng, Lv, Zhong and Peng.)

Background: Pro-inflammatory cytokines such as interleukin (IL)-6 and tumor necrosis factor (TNF)-α are elevated in response to psychosocial stress; however, less is known about other inflammatory markers., Methods: We explored response to the Trier Social Stress Test (TSST) of 16 cytokines and growth factors in patients with major depressive disorder (MDD, n = 12) vs. healthy volunteers (HV, n = 16). Outcomes were baseline and post-stress levels estimated by area under the curve (AUC i ) and peak change over 3 timepoints. We also explored correlations between biomarkers and clinical characteristics., Results: Baseline concentrations were higher in MDD for platelet-derived growth factor (PDGF)-AB/BB (p = 0.037, d = 0.70), granulocyte-macrophage colony-stimulating factor (GM-CSF, p = 0.033, d = 0.52), and IL-8 (p = 0.046, d = 0.74). After TSST, AUC i was higher in MDD for GM-CSF (p = 0.003, d = 1.21), IL-5 (p = 0.014, d = 1.62), and IL-27 (p = 0.041, d = 0.74). In MDD, depression severity correlated positively with soluble CD40L (sCD40L) for AUC i (Spearman's ρ = 0.76, p = 0.004) and with baseline vascular endothelial growth factor A (VEGFA, r = 0.85, p < 0.001), but negatively with baseline monokine induced by gamma interferon (MIG, aka CXCL9; r = -0.77, p = 0.003)., Conclusions: Effect sizes were robust in this exploratory study, although interpretation of the results must be cautious, given small sample size and multiple comparisons. Differential study of stress-induced biomarkers may have important ramifications for MDD treatment., Competing Interests: Declaration of competing interest JJM receives royalties for commercial use of the C-SSRS from the Research Foundation for Mental Hygiene. HG and spouse own stocks in Illumina, Inc. and IBM, Inc. JGK and spouse own stock in Pfizer and Zoetis. All other authors have no conflicts to report., (Copyright © 2023. Published by Elsevier Ltd.)