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Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis (1). Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1β [...]

IL-17-producing [CD8.sup.+] T (Tc17) cells are detectible in multiple sclerosis (MS) lesions; however, their contribution to the disease is unknown. To identify functions of Tc17 cells, we induced EAE, a [...]

Background Acute pyelonephritis (APN) is one of the most significant bacterial infections in infancy and early childhood, and can lead to permanent kidney damage and chronic renal failure. Objective To evaluate interleukin-6 (IL-6) and interleukin-8 (IL-8) levels in the urine of children with renal scarring (RS), searching for clinical information about the immunoinflammatory process that contributes to RS. Methods Urine concentrations of IL-6 and IL-8 were evaluated in 50 children, 33 with RS detected after an episode of acute pyelonephritis (group A) and 17 children with a history of acute pyelonephritis, but without RS (group B). These children were divided into four groups: [groupA.sub.1], 23 children with RS and vesicoureteral reflux (VUR); [groupA.sub.2], 10 children with RS without VUR; group [B.sub.1], 13 children without RS and without VUR; group [B.sub.2], 4 children without RS, but with VUR. None of them had had urinary tract infection for a minimum of 6 months. To avoid dilution effects, urinary levels of IL-6 and IL-8 were expressed as the ratio of cytokine to urinary creatinine (pg/mg). Results Urinary IL-8 levels were below the lower detection limit in all samples. IL-6 was detectable in the majority of children with RS and below the detection limits in the urine samples of children without RS. There were no statistically significant differences between urinary interleukin-6 levels in children with and those without VUR. There was a significant relationship between the grade of renal scars, the time passed since the last episode of acute pyelonephritis and the urinary levels of IL-6 (p Conclusion Further experimental studies are required to demonstrate the correlation between histopathology and urinary cytokine levels. Keywords Renal scarring * Interleukin-6 * Interleukin-8 * Vesicoureteral reflux, Introduction Acute pyelonephritis (APN) is one of the most important bacterial infections in infancy and early childhood. The incidence of febrile urinary tract infections (UTIs) is 1-2/ 1,000 children [1]. [...]

Urine IL-8 concentrations are known to be elevated in urinary tract infection (UTI), as well as in vesicoureteral reflux (VUR) even in the absence of infection. In this study we further investigated urine IL-8 in infants with congenital anomalies of the kidneys and urinary tract and with antenatally diagnosed isolated pelvic dilatation. Urine IL8 was measured in 159 infants aged 1 month to 1 year with acute UTI (group A, n=26), resolved UTI (group B, n=16), VUR without recent UTI (group C, n=44), non-VUR congenital urinary anomalies without recent UTI (group D, n=30), isolated antenatal pelvic dilatation (group E, n=14) and in infants without known urinary tract condition (control group F, n=29). Median values of urine IL-8/creatinine levels were 61.5, 4.64, 15.5, 14.3, 1.06 and 4.19 pg/µmol in groups A, B, C, D, E and F respectively. Compared with the control group, urine IL-8 was elevated in infants with acute UTI, VUR without acute UTI and congenital anomalies without acute UTI (p Keywords Biomarkers * Congenital urinary tract anomalies * Interleukin-8 * Urinary tract infection * Vesicoureteral reflux, Introduction Cytokines are known to modulate the inflammatory response in urinary tract infection (UTI) and associated renal damage and fibrosis, but less is known on their role in non-infectious urinary [...]

Inflammatory cytokines mediate inflammatory bowel diseases (IBDs) and cytokine blocking therapies often ameliorate the disease severity. IL-32 affects inflammation by increasing the production of IL-1, TNF[alpha], and several chemokines. Here, we investigated the role of IL-32 in intestinal inflammation by generating a transgenic (TG) mouse expressing human IL-32[gamma] (IL-32[gamma] TG). Although IL-32[gamma] TG mice are healthy, constitutive serum and colonic tissue levels of TNF[alpha] are elevated. Compared with wild-type (WT) mice, IL-32[gamma] TG mice exhibited a modestly exacerbated acute inflammation early following the initiation of dextran sodium sulfate (DSS)-induced colitis. However, after 6 d, there was less colonic inflammation, reduced tissue loss, and improved survival rate compared with WT mice. Associated with attenuated tissue damage, colonic levels of TNF[alpha] and IL-6 were significantly reduced in the IL-32[gamma] TG mice whereas IL-10 was elevated. Cultured colon explants from IL-32[gamma] TG mice secreted higher levels of IL-10 compared with WT mice and lower levels of TNF[alpha] and IL-6. Constitutive levels of IL-32[gamma] itself in colonic tissues were significantly lower following DSS colitis. Although the highest level of serum IL-32[gamma] occurred on day 3 of colitis, IL-32 was below constitutive levels on day 9. The ability of IL-32[gamma] to increase constitutive IL-10 likely reduces TNF[alpha], IL-6, and IL-32 itself accounting for less inflammation. In humans with ulcerative colitis (UC), serum IL-32 is elevated and colonic biopsies contain IL-32 in inflamed tissues but not in uninvolved tissues. Thus IL-32[gamma] emerges as an example of how innate inflammation worsens as well as protects intestinal integrity. innate immunity | intestinal barrier | Crohn's disease doi/ 10.1073/pnas.1015418107

The respiratory distress syndrome (RDS) contributes to perinatal morbidity and mortality associated with preterm birth. Surfactant protein B (SP-B) is decreased in RDS. Both maternal antenatal steroid administration and chorioamnionitis reduce the incidence and severity of RDS. An important mediator in chorioamnionitis is IL-6 using the JAK-STAT signaling pathway for signal transduction. We hypothesized that the steroids, betamethasone (BTM) and dexamethasone (DXM), and IL-6 had synergistic effects on SP-B gene expression and STAT3 phosphorylation in H441 cells. DXM and BTM increased SP-B mRNA levels by 16.5 (13.3)-fold and IL-6 alone by 2.3-fold. After 48-h exposure of cells to DXM or BTM, IL-6 caused a significantly greater increase in SP-B mRNA levels (28.1-fold) than IL-6 or glucocorticolds alone. Whereas IL-6 stimulated tyrosine phosphorylation of STAT3 in a time- and dose-dependent way, DXM and BTM had no effect on STAT3 phosphorylation. Both DXM and BTM could potentiate IL-6-induced phosphorylation of STAT3. The synergism of glucocorticoids and IL-6 on SP-B gene expression and the effect of glucocorticoids on IL-6-induced STAT3 phosphorylation could be blocked by a JAK inhibitor. Expression level analysis showed that glucocorticoids increased the expression of the IL-6-binding s-subunit receptor (IL-6R) on mRNA and protein level. Our findings could represent an example of a pulmonary regulation system in which one role of glucocorticoids is to increase the effect of a cytokine by upregulation of its receptor. The described in vitro interaction of IL-6 and glucocorticoids could help explain the clinical observation that prenatal inflammation in preterm babies with antenatal steroid administration can attenuate severity of RDS. dexamethasone; betamethasone; surfactant protein B; interleukin-6 receptor; STAT3; Janus kinase; respiratory distress syndrome doi: 10.1152/ajplung.00055.2010.

Background. Recent studies have suggested that inflammation may play an important role in aging and the development of disabilities, but knowledge about its importance in the development of muscle weakness and functional disabilities in very old people is limited. This study examined associations between inflammatory markers and physical performance among nonagenarians. Methods. The population-based sample consisted of 197 women and 65 men aged 90 years. Physical performance was assessed according to the Barthel Index, the chair stand, and handgrip strength. Plasma levels of interleukin-6 (IL-6), interleukin-1 receptor antagonist (IL-1Ra), and C-reactive protein (CRP) were determined. Results. A gender-adjusted linear regression model showed that high levels of CRR IL-6, and IL-IRa were significantly associated with poor handgrip strength (p = .041, p = .023, p < .001, respectively). After adjustment for diseases, smoking and physical exercise high levels of IL-6 and IL-IRa were still significantly associated with poor hand grip strength (p = .048, p = .004, respectively). In the gender-adjusted model, high levels of CRP, IL-6, and IL-IRa were significantly associated with a worse Barthel Index (p = .009, p = .004, p = .004, respectively). High levels of CRP and IL-6 were still significantly associated with a worse Barthel Index after adjusted for diseases, smoking and physical exercise (p = .034, p = .041, respectively). In the chair stand, no significant association with inflammatory markers was found. Conclusions. Associations between high levels of inflammatory markers and worse handgrip strength as well as a worse Barthel index result were evident among nonagenarians. However, the association with the chair stand was not significant. doi: 10.1093/gerona/glq056

Interleukin(IL)-4 and IL-13 signal through heterodimeric receptors containing a common IL-4 receptor-[alpha] (IL-4R[alpha]) subunit, which is important for protection against helminth infections, including schistosomiasis. Previous studies demonstrated important roles for IL-4R[alpha]-responsive hematopoietic cells, including T cells and macrophages in schistosomiasis. In this study, we examined the role of IL-4R[alpha] responsiveness by nonhematopoietic smooth muscle cells during experimental acute murine schistosomiasis. Comparative Schistosoma mansoni infection studies with smooth muscle cell-specific 1L-4R[alpha]-deficient ([SM-MHC.sup.cre][IL-4R[alpha].sup.-/flox]) mice, heterozygous control ([IL-4R[alpha].sup.-/flox]) mice, and global IL-4R[alpha]-deficient ([IL-4R[alpha].sup.-/-]) mice were conducted. S. numsoni-infected [SM-MHC.dup.cre][IL-4R[alpha].sup.-/flox] mice showed increased weight loss and earlier mortalities compared with [IL-4R[alpha].sup.-/flox] mice, despite comparable [T.sub.H]2/type 2 immune responses. In contrast to highly susceptible IL-4R[alpha]-deficient mice, increased susceptibility in [SM-MHC.sup.cre][IL-4R[alpha].sup.-/flox] mice was not accompanied by intestinal tissue damage and subsequent sepsis. However, both susceptible mutant mouse strains failed to efficiently expel eggs, demonstrated by egg reduction in the feces compared with control mice. Reduced egg expulsion was accompanied by impaired IL-4/IL-13-mediated hypercontractile intestinal responses, which was present in the more resistant control mice. Together, we conclude that IL-4R[alpha] responsiveness by smooth muscle cells and subsequent IL-4- and IL-13-mediated hypercontractility are required for host protection during acute schistosomiasis to efficiently expel S. mansoni eggs and to prevent premature mortality. Schistosoma mansoni; helminth; intestine; murine; Nippostrongylus brasiliensis doi: 10.1152/ajpgi.00321.2009.

The objective of this study was to assess the urine levels of interleukin-6 (IL-6) and interleukin-8 (IL-8) as noninvasive markers of vesicoureteral reflux (VUR) and renal parenchymal scarring (RPS) in children in the absence of a recent urinary tract infection (UTI) episode. Urine concentrations of IL-6 and IL-8 in 114 children aged 1 month to 16 years were evaluated. The children were divided into four groups: group 1, 26 children with VUR and RPS; group 2, 27 children with VUR without RPS; group 3, 34 children with RPS without VUR, group 4, 27 children without VUR and RPS, as the control group. After the first assessment, the children were divided into four larger groups for comparison purposes: group A (groups 1 + 2), 53 children with VUR; group B (groups 3 + 4), 61 children without VUR; group C (groups 1 + 3), 60 children with RPS; group D (groups 2 + 4), 54 children without RPS. Urinary IL-6 and IL-8 concentrations were determined. To avoid dilution effects and to the standardize samples, urinary levels of IL-6 and IL-8 were expressed as the ratio of cytokine to urinary creatinine (pg/mg). The median urine IL-6/creatinine was significantly higher in patients with VUR than in those without VUR (5.72 vs. 3.73). In patients with VUR, there was a significant but rather weak correlation between IL-6/creatinine concentrations and the reflux grade (p < 0.05, R = 0.305). The median urine IL-8/ creatinine was significantly higher in patients with RPS than in those without RPS (43.12 vs. 16.36). In patients with RPS, there was a significant but rather weak correlation between IL-8/creatinine concentrations and the renal scar grade (p < 0.05, R = 0.251). The results of this study provide preliminary evidence that children with VUR have a high urine IL-6 concentration, whereas children with RPS have a high urine IL-8 concentration. Keywords Interleukin-6 * Interleukin-8 * Reflux Nephropathy * Urinary tract infection * Vesicoureteral reflux, Introduction Urinary tract infection (UTI) in infants and children is a relatively common problem which, if not treated early and properly, may lead to renal scarring and hypertension. The incidence [...]

IL-33 is a novel member of the IL-1 family and ligand for the IL-1 receptor-related protein, ST2. Recent evidence suggests that the IL33/ST2 axis plays a critical role in several autoimmune and inflammatory disorders; however, its role in inflammatory bowel disease (IBD) has not been clearly defined. We characterized IL-33 and ST2 expression and modulation after conventional anti-TNF therapy in Crohn's disease and ulcerative colitis (UC) patients and investigated the role of IL-33 in SAMP1/YitFc (SAMP) mice, a mixed Th1/Th2 model of IBD. Our results showed a specific increase of mucosal IL-33 in active UC, localized primarily to intestinal epithelial cells (IEC) and colonic inflammatory infiltrates. Importantly, increased expression of full-length IL-33, representing the most bioactive form, was detected in UC epithelium, whereas elevated levels of cleaved IL-33 were present in IBD serum. ST2 isoforms were differentially modulated in UC epithelium, and sST2, a soluble decoy receptor with anti-inflammatory properties, was also elevated in IBD serum. Infliximab (anti-TNF) treatment of UC decreased circulating IL-33 and increased sST2, whereas stimulation of HT-29 IEC confirmed IL-33 and sST2 regulation by TNF. Similarly, IL-33 significantly increased and correlated with disease severity, and potently induced IL-5, IL-6, and IL-17 from mucosal immune cells in SAMP mice. Taken together, the IL-33/ST2 system plays an important role in IBD and experimental colitis, is modulated by antiTNF therapy, and may represent a specific biomarker for active UC. inflammatory bowel disease/anti-TNF therapy/SAMP1/YitFc mouse model doi/ 10.1073/pnas.0912678107

The intrinsic role of endogenous IL-17A in spontaneous intestinal tumorigenesis has not been addressed previously to our knowledge. Ablation of IL-17A significantly reduced tumor development in mice bearing a heterozygote mutation in the adenomatous polyposis coli (APC) gene ([Apc.sup.Min/+] mice). There was also a decrease in inflammatory cytokines and proinflammatory mediators, reduced infiltration of lymphocytes including T cells, and preservation of intestinal architecture and the presence of APC protein in intestinal epithelial cells. Interestingly, IL-17A ablation also corrected immunological abnormalities such as splenomegaly and thymic atrophy in [Apc.sub.Min/+] mice. CD4 T cells from [Apc.sub.Min/+] mice showed hyperproliferative potential in vitro and in vivo and increased levels of IL-17A and IL-10. The effector CD4 T cells from [Apc.sup.Min/+] mice were more resistant to regulatory T cell-mediated suppression. Finally, these CD4 T cells induced colitis in immunodeficient mice upon adoptive transfer, whereas the ablation of IL-17A in CD4 T cells in [Apc.sup.Min/+] mice completely abolished this pathogenic potential in vivo. Taken together, our results show that CD4 T cell-derived IL-17A promotes spontaneous intestinal tumorigenesis with altered functions of CD4 T cells in [Apc.sup.Min/+] mice. inflammation | T cells | colon cancer www.pnas.org/cgi/doi/10.1073/pnas.0912675107

The peptide substance P (SP) has been implicated in inflammatory conditions, such as psoriasis, where mast cells and VEGF are increased. A relationship between SP and VEGF has not been well studied, nor has any interaction with the proinflammatory cytokines, especially IL-33. Here we report that SP (0.1-10 [micro]M) induces gene expression and secretion of VEGF from human LAD2 mast cells and human umbilical core blood-derived cultured mast cells (hCBMCs). This effect is significantly increased by coadministration of IL-33 (5-100 ng/mL) in both cell types. The effect of SP on VEGF release is inhibited by treatment with the NK-1 receptor antagonist 733,060. SP rapidly increases cytosolic calcium, and so does IL33 to a smaller extent; the addition of IL-33 augments the calcium increase. SP-induced VEGF production involves calcium-dependent PKC isoforms, as well as the ERK and JNK MAPKs. Gene expression of IL-33 and histidine decarboxylase (HDC), an indicator of mast cell presence/activation, is significantly increased in affected and unaffected (at least 15 cm away from the lesion) psoriatic skin, as compared with normal control skin. Immunohistochemistry indicates that IL-33 is associated with endothelial cells in both the unaffected and affected sites, but is stronger and also associated with immune cells in the affected site. These results imply that functional interactions among SP, IL-33, and mast cells leading to VEGF release contribute to inflammatory conditions, such as the psoriasis, a nonallergic hyperproliferative skin inflammatory disorder with a neurogenic component. inflammation | cytokines | IL-1 | innate immunity | stress doi/10.1073/pnas.1000803107

Immune-suppressive cell populations, including Tregs and suppressor monocytes, have been implicated in long-term survival of allografts in both human transplant recipients and animal models. The factors that drive differentiation and function of these cell populations are not completely understood. In this issue, Bezie and colleagues identify IL-34 as an important mediator of allograft tolerance in a rat model of heart transplantation. Their data support a model in which IL-34 production by Tregs promotes a population of suppressive macrophages that in turn promote Treg differentiation. The results of this study support further exploration of the immunosuppressive properties of IL-34., Tregs and immune tolerance Tolerance to self- and foreign antigens is created by a combination of the deletion of antigen-reactive T cells and control of the remaining cells by a [...]

The therapeutic efficacy of anticancer chemotherapies may depend on dendritic cells (DCs), which present antigens from dying cancer cells to prime tumor-specific interferon-[gamma] (IFN-[gamma])-producing T lymphocytes. Here we show that [...]

The article discusses the concept of distinct types of helper T cells, such as the Interleukin-17 and Type 17 helper T cells. The sources and key functions of key helper T cells and their therapeutic potential are highlighted.

[[alpha].sub.1]-Antitrypsin (AT) is a major elastase inhibitor within the lung. Oxidation of critical methionine residues in AT generates oxidized AT (Ox-AT), which has a greatly diminished ability to inhibit neutrophil elastase. This process may contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD) by creating a functional deficiency of AT permitting lung destruction. We show here that Ox-AT promotes release of human monocyte chemoattractant protein-1 (MCP-1) and IL-8 from human lung type epithelial cells (A549) and normal human bronchial epithelial (NHBE) cells. Native, cleaved, polymeric AT and secretory leukoproteinase inhibitor (SLPI) and oxidized conformations of cleaved, polymeric AT and SLPI did not have any significant effect on MCP-1 and IL-8 secretion. These findings were supported by the fact that instillation of Ox-AT into murine lungs resulted in an increase in JE (mouse MCP-1) and increased macrophage numbers in the bronchoalveolar lavage fluid. The effect of Ox-AT was dependent on NF-[kappa]B and activator protein-1 (AP-1)/JNK. These findings have important implications. They demonstrate that the oxidation of methionines in AT by oxidants released by cigarette smoke or inflammatory cells not only reduces the antielastase lung protection, but also converts AT into a proinflammatory stimulus. Ox-AT generated in the airway interacts directly with epithelial cells to release chemokines IL-8 and MCP-1, which in turn attracts macrophages and neutrophils into the airways. The release of oxidants by these inflammatory cells could oxidize AT, perpetuating the cycle and potentially contributing to the pathogenesis of COPD. Furthermore, these data demonstrate that molecules such as oxidants, antiproteinases, and chemokines, rather than act independently, are likely to interact to cause emphysema. chronic obstructive pulmonary disease; interleukin-8; oxidants

Helicobacter pylori is a major cause of the transdifferentiation into intestinal metaplasia that may develop gastric cancer. However, the molecular pathogenesis of this transdifferentiation is poorly understood. A SRY-related HMG box protein Sox2 is an essential transcription factor of organ development in brain, lung, and stomach. Our aim of this study was to investigate the mechanism responsible for regulation of Sox2 in host Thl-dominant response to H. pylori. Sox2 protein was immunohisto-chemically expressed in both human oxyntic and pyloric glands with H. pylori infection, but not in intestinal metaplasia. Western immunoblotting of gastric epithelial cell lines showed that IL-4, a Th2-related cytokine, dose dependently enhanced Sox2 expression among H. pylori infection-mediated cytokines. Small changes of Sox2 expression were observed after each treatment with [FN-[gamma], IL-1[beta], or TNF-[alpha]. IL-4-mediated Sox2 induction was suppressed by the inhibition of STAT6 activation with STAT6 RNA interference, and electrophoretic mobility shift assay indicated that activation of the Sox2 promoter by 1L-4 occurred through the action of STAT6. Furthermore, H. pylori and IFN-[gamma] inhibited the phosphorylation of STAT6, resulting in the suppression of IL-4-mediated Sox2 expression. Immunofiistochemical analyses showed significantly the suppressed STAT6 activity in H. pylori-infected human gastric mucosa. Additionally, downregulation of Sox2 by knockdown experiments led to intestinal phenotype with expressions of Cdx2 and MUC2. These results suggest that H. pylori and IFN-[gamma] interfere with the differentiation into oxyntic and pyloric glands by the downregulation of Sox2 on IL-4/STAT6 signaling, which may contribute to the transdifferentiation into intestinal metaplasia. transdifferentiation; STAT6 signaling; Cdx2

Hepatic preconditioning has emerged as a promising strategy of activating natural pathways to augment tolerance to liver ischemia-reperfusion (IR) injury. Liver-resident natural killer T (NKT) cells play an important role in modulating the local immune and inflammatory responses. This work was aimed to investigate whether preactivation of NKT cells could provide a beneficial 'preconditioning' effect to ameliorate the subsequent hepatic IR injury. To selectively activate NKT cells, C57BL/6 mice were treated intraperitoneally with the glycolipid antigen a-galactosylceramide ([alpha]-GalCer) 1 h prior to hepatic ischemia. Significantly reduced liver IR injury was observed in mice pretreated with aGalCer, and this protective effect was specifically abrogated by a CD1d blocking antibody. Serum TNF-[alpha], IFN-[gamma] and IL-13 levels were markedly increased shortly after [alpha]-GalCer injection. Pretreatment with a neutralizing antibody against TNF-[alpha] or IFN-[gamma] did not influence the protective effect of [alpha]-GalCer preconditioning, whereas preadministration of an IL-13 neutralizing antibody completely abolished the effect. Treatment with [alpha]-GalCer also led to an increased expression of adenosine [A.sub.2A] receptor ([A.sub.2A]R) in the liver, and blockade of [A.sub.2A]R by SH58261 diminished [alpha]-GalCer pretreatment-mediated attenuation of liver IR injury. In contrast, administration of the selective [A.sub.2A]R agonist CGS21680 reversed the counteracting effect of the IL-13 neutralizing antibody on [alpha]-GalCer preconditioning. Additionally, [alpha]-GalCer pretreatment was associated with a decreased neutrophil accumulation in the ischemic liver. These findings provide the first evidence that hepatic preconditioning by prcactivation of NKT cells with [alpha]-GalCer protects the liver from IR injury via an IL-13 and adenosine [A.sub.2A]R-dependent mechanism. liver protection; natural killer T cells; glycolipid; Thl/Th2 cytokines; [alpha]-galactosylceramide

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.tips.2009.05.006 Byline: Giovanni Monteleone (1), Francesco Pallone (1), Thomas T. Macdonald (2) Abstract: Cytokines have a decisive role in initiating and shaping pathologic responses in patients with various immune-inflammatory diseases. Recent studies indicate that interleukin (IL)-21, a cytokine produced mostly by activated CD4+ T cells, participates in the tissue damage in various tissues, owing to its ability to regulate the function of immune and non-immune cells. For instance, IL-21 controls the differentiation and functional activity of T cells, B cells and NK cells, limits the differentiation of inducible regulatory T cells (Tregs), and makes T cells resistant to the Treg-mediated immunesuppression. It also stimulates epithelial cells and fibroblasts to produce inflammatory mediators. Here, we focus on data supporting the pathogenic role of IL-21 in human inflammatory diseases and discuss pre-clinical studies that suggest that neutralization of IL-21 in vivo could be a new biological therapy to combat immune-mediated pathologies, such as inflammatory bowel diseases, diabetes, rheumatoid arthritis and systemic lupus erythematosus. Author Affiliation: (1) Department of Internal Medicine, University of Rome 'Tor Vergata', Rome 00133, Italy (2) Institute of Cell and Molecular Science, Bart's and the London School of Medicine and Dentistry, London, E1 2AT, UK

IL-17 and IL-22 have been shown to increase protection against certain bacteria and fungal pathogens in experimental models. However, no human studies have demonstrated a crucial role of IL-17 and IL-22 in protection against infections. We show here that Leishmania donovani, which can cause the lethal visceral disease Kala Azar (KA), stimulates the differentiation of Th17 cells, which produce IL-17, IL-22, and IFN-[gamma]. Analysis of Th1, Th2, and Th17 cytokine responses by cultured PBMCs from individuals in a cohort of subjects who developed KA or were protected against KA during a severe outbreak showed that IL-17 and IL-22 were strongly and independently associated with protection against KA. Our results suggest that, along with Th1 cytokines, IL-17 and IL-22 play complementary roles in human protection against KA, and that a defect in Th17 induction may increase the risk of KA., Introduction Th17 cells are independently regulated [CD4.sup.+] T cells initially characterized as producing cytokines in the IL-17 family. They are highly proinflammatory and stimulate the production, by endothelial and epithelial [...]

Psoriasis is a common immune-mediated chronic inflammatory skin disorder, but the mechanisms of pathogenesis are still poorly understood. IL-23 is expressed in psoriatic skin, and IL-23 injection produces IL-22-dependent psoriasiform changes in mouse skin. Th17 cells produce IL-22 and display CCR6, the CCL20 receptor; [CCR6.sup.+] T cells and CCL20 are abundant in psoriatic skin. We investigated a possible role for CCR6 in recruiting Th17 cells and producing psoriasiform pathology by injecting IL-23 into the skin of WT and Ccr6-/- mice. Unlike for WT mice, IL-23-injected ears of Ccr6-/- mice showed neither substantial epidermal/dermal changes nor increased Il22 mRNA expression. However, injection of IL-22 yielded equivalent psoriasiform changes in WT and Ccr6-/- mice. Surprisingly, IL-23-injected ears of WT and Ccr6-/- mice contained similar numbers of Th cells able to make IL-17A and/or IL-22. Furthermore, in ears of Rag1-/- mice, IL-23 initially induced skin changes and levels of Il22 mRNA that were indistinguishable from WT mice, revealing at least one non--T cell source for IL-22. We conclude that CCR6 is essential in a model of IL-23-induced, IL-22-mediated dermatitis, which develops in sequential T cell--independent and T cell--dependent phases. These findings reveal an expanded role for CCR6 in IL-23-related responses and identify CCR6 as a potential therapeutic target in psoriasis., Introduction Psoriasis is one of the most common immune-mediated chronic inflammatory skin disorders in adults, affecting 1%-2% of white individuals, with a considerable impact on quality of life (1). Defining [...]

Massive liver resection and small-for-size liver transplantation pose a therapeutic challenge, due to increased susceptibility of the remnant/graft to ischemia reperfusion injury (IRI) and impaired regeneration. We investigated the dual role of complement in IRI versus regeneration in mice. Complement component 3 (C3) deficiency and complement inhibition with complement receptor 2-complement receptor 1-related protein y (CR2-Crry, an inhibitor of C3 activation) provided protection from hepatic IRI, and while C3 deficiency also impaired liver regeneration following partial hepatectomy (PHx), the effect of CR2-Crry in this context was dose dependent. In a combined model of IRI and PHx, either C3 deficiency or high-dose CR2-Crry resulted in steatosis, severe hepatic injury, and high mortality, whereas low-dose CR2-Crry was protective and actually increased hepatic proliferative responses relative to control mice. Reconstitution experiments revealed an important role for the C3a degradation product acylation-stimulating protein (ASP) in the balance between inflammation/injury versus regeneration. Furthermore, liver regeneration was dependent on the putative ASP receptor, C5L2. Several potential mechanisms of hepatoprotection and recovery were identified in mice treated with low-dose CR2-Crry, including enhanced IL-6 expression and STAT3 activation, reduced hepatic ATP depletion, and attenuated oxidative stress. These data indicate that a threshold of complement activation, involving ASP and C5L2, promotes liver regeneration and suggest a balance between complement-dependent injury and regeneration., Introduction Liver resection has become an increasingly safe procedure, but certain procedures remain high risk, such as massive liver resection and small-for-size (SFS) liver transplantation (1), (2), (3). Massive hepatic [...]

Phase II clinical trials revealed that the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath-1H) is highly effective in the treatment of early relapsing-remitting multiple sclerosis. However, 30% of patients develop autoimmunity months to years after pulsed exposure to alemtuzumab, usually targeting the thyroid gland and, more rarely, blood components. In this study, we show that autoimmunity arose in those patients with greater T cell apoptosis and cell cycling in response to alemtuzumab-induced lymphocyte depletion, a phenomenon that is driven by higher levels of IL-21. Before treatment, patients who went on to develop secondary autoimmunity had more than 2-fold greater levels of serum IL-21 than the nonautoimmune group. We suggest that serum IL-21 may, therefore, serve as a biomarker for the risk of developing autoimmunity months to years after alemtuzumab treatment. This has implications for counseling those patients with multiple sclerosis who are considering lymphocyte-depleting therapy with alemtuzumab. Finally, we demonstrate through genotyping that IL-21 expression is genetically predetermined. We propose that, by driving cycles of T cell expansion and apoptosis to excess, IL-21 increases the stochastic opportunities for T cells to encounter self antigen and, hence, for autoimmunity., Introduction Autoimmunity arising in the context of lymphopenia is well recognized experimentally but rarely encountered and, hence, difficult to study in humans. We have identified an example of predictable autoimmunity [...]

Inflammatory mechanisms contribute to atherogenesis. Monocyte chemoattractant protein (MCP)-1 and IL-6 are potent mediators of inflammation. Both contribute to early atherogenesis by luring monocytes and regulating cell functions in the vessel wall. MCP-1 and IL-6 production resulting from the interaction of invading monocytes with local vessel wall cells may accelerate atherosclerosis. We investigated the influence of the interaction of human vascular smooth muscle cells (SMCs) with human mononuclear cells (MNCs) or monocytes on IL-6 and MCP-1 production in a coculture model. Interaction synergistically enhanced IL-6 and MCP-1 production (up to 30- and 10-fold, respectively) compared with separately cultured cells. This enhancement was mediated by CD14-positive monocytes. It was dependent on the SMC-to-MNC/monocyte ratio, and as few as 0.2 monocytes/SMC induced the synergism. Synergistic IL-6 production was observed at the protein, mRNA, and functional level. It was mediated by soluble factors, and simultaneous inhibition of IL-1, TNF-[alpha], and IL-6 completely blocked the synergism. IL-1, TNF-[alpha], and IL-6 were present in the cultures. Blockade of the synergism by soluble glycoprotein 130Fc/soluble IL-6 receptor, as well as the induction of synergistic IL-6 production by costimulation of SMCs with IL-1, TNF-[alpha], and hyper-IL-6, suggested the involvement of IL-6 trans-signaling. The contribution of IL-6 was consistent with enhanced STAT3 phosphorylation. The present data suggest that SMC/monocyte interactions may augment the proinflammatory status in the tissue, contributing to the acceleration of early atherogenesis. inflammation; monocytes/macrophages; chemokines; cytokines; lipo-polysaccharide; interleukin-6; monocyte chemoattractant protein-1

HIV infection results in [CD4.sup.+] T cell deficiency, but efficient combination antiretroviral therapy (c-ART) restores T cells and decreases morbidity and mortality. However, immune restoration by c-ART remains variable, and prolonged T cell deficiency remains in a substantial proportion of patients. In a prospective open-label phase I/IIa trial, we evaluated the safety and efficacy of administration of the T cell regulator IL-7. The trial included 13 c-ART--treated HIV-infected patients whose [CD4.sup.+] cell counts were between 100 and 400 cells/[mu]l and plasma HIV RNA levels were less than 50 copies/ml. Patients received a total of 8 subcutaneous injections of 2 different doses of recombinant human IL-7 (rhIL-7; 3 or 10 [micro]g/kg) 3 times per week over a 16-day period. rhIL-7 was well tolerated and induced a sustained increase of naive and central memory [CD4.sup.+] and [CD8.sup.+] T cells. In the highest dose group, 4 patients experienced transient increases in viral replication. However, functional assays showed that the expanded T cells responded to HIV antigen by producing IFN-[gamma] and/or IL-2. In conclusion, in lymphopenic HIV-infected patients, rhIL-7 therapy induced substantial functional and quantitative changes in T cells for 48 weeks. Therefore, patients may benefit from intermittent therapy with IL-7 in combination with c-ART., Introduction Infection with HIV is characterized by chronic T cell depletion and increased risk of illness and opportunistic infection. Effective treatment of HIV infection with combination antiretroviral therapy (c-ART) suppresses [...]

Increasing evidence demonstrates that interleukin (IL)-32 is a proinflammatory cytokine, inducing IL-1[alpha], IL-1[beta], IL-6, tumor necrosis factor (TNF)-[alpha], and chemokines via nuclear factor (NF)-[kappa]B, p38 mitogen-activated protein kinase (MAPK), and activating protein (AP)-1 activation. Here we report that IL-32 is expressed and is also functional in human vascular endothelial cells (EC) of various origins. Compared with primary blood monocytes, high levels of IL-32 are constitutively produced in human umbilical vein EC (HUVEC), aortic macrovascular EC, and cardiac as well as pulmonary microvascular EC. At concentrations as low as 0.1 ng/ml, IL-1[beta] stimulated IL-32 up to 15-fold over constitutive levels, whereas 10 ng/ml of TNF[alpha] or 100 ng/ml of lipopolysaccharide (LPS) were required to induce similar quantities of IL-32. IL-1[beta]-induced IL-32 was reduced by inhibition of the I[kappa]B kinase-[beta]/NF-[kappa]B and ERK pathways. In addition to IL-1[beta], pro-coagulant concentrations of thrombin or fresh platelets increased IL-32 protein up to 6-fold. IL-1[beta] and thrombin induced an isoformswitch in steady-state mRNA levels from IL-32[alpha]/[gamma] to [beta]/[epsilon]. Adult EC responded in a similar fashion. To prove functionality, we silenced endogenous IL-32 with siRNA, decreasing intracellular IL-32 protein levels by 86%. The knockdown of IL-32 resulted in reduction of constitutive as well as IL-1[beta]-induced intercellular adhesion molecule-1 (ICAM-1) (of 55% ancl 54%, respectively), IL-1[alpha] (of 62% and 43%), IL-6 (of 53% and 43%), and IL-8 (of 46% and 42%). In contrast, the anti-inflammatory/anti-coagulant CD141/thrombomodulin increased markedly when IL-32 was silenced. This study introduces IL-32 as a critical regulator of endothelial function, expanding the properties of this cytokine relevant to coagulation, endothelial inflammation, and atherosclerosis. Atherosclerosis | Coagulation | Inflammation

The clear association of Th17 cells with autoimmune pathogenicity implicates Th17 cytokines as critical mediators of chronic autoimmune diseases such as EAE. To study the impact of IL-17A on CNS inflammation, we generated transgenic mice in which high levels of expression of IL-17A could be initiated after Cre-mediated recombination. Although ubiquitous overexpression of IL-17A led to skin inflammation and granulocytosis, T cell--specific IL-17A overexpression did not have a perceptible impact on the development and health of the mice. In the context of EAE, neither the T cell--driven overexpression of IL-17A nor its complete loss had a major impact on the development of clinical disease. Since IL-17F may be able to compensate for the loss of IL-17A, we also generated IL-17F--deficient mice. This strain was fully susceptible to EAE and displayed unaltered emergence and expansion of autoreactive T cells during disease. To eliminate potential compensatory effects of either cytokine, we treated IL-17F--deficient mice with antagonistic monoclonal antibodies specific for IL-17A and found again only a minimal beneficial impact on disease development. We conclude therefore that both IL-17A and IL-17F, while prominently expressed by an encephalitogenic T cell population, may only marginally contribute to the development of autoimmune CNS disease., Introduction MS and its animal model EAE are characterized by the invasion of self-reactive Th cells into the CNS, leading to demyelination, axonal loss, and neurological impairment (1). Upon activation, [...]

The expression of Ig-like transcript (ILT) inhibitory receptors is a characteristic of tolerogenic dendritic cells (DCs). However, the mechanisms of modulation of DCs via ILT receptors remain poorly defined. HLA-G is a preferential ligand for several ILTs. Recently, we demonstrated that triggering of ILT4 by HLA-G1 inhibits maturation of human monocyte-derived conventional DCs and murine DCs from ILT4 transgenic mice, resulting in diminished expression of MHC class II molecules, CD80 and CD86 costimulatory molecules, and prolongation of skin allograft survival. Different isoforms of HLA-G have diverse effects on the efficiency to induce ILT-mediated signaling. In this work, we show that HLA-G1 tetrameric complex and HLA-G5 dimer, but not HLA-G5 monomer, induce strong ILT-mediated signaling. We determined that the arrest of maturation of ILT4-positive DCs by HLA-G ligands involves the IL-6 signaling pathway and STAT3 activation. Ligation of ILT4 with HLA-G on DCs results in recruitment of SHP-1 and SHP-2 protein tyrosine phosphatases. We propose a model where SHP-2 and the IL-6-STAT3 signaling pathway play critical roles in the modulation of DC differentiation by ILT4 and HLA-G. immunomodulation | inhibitory receptor

Chronic inflammation in the stomach induces cellular transformation and gastric cancer primarily in the distal stomach or antrum. In this issue of the JCI, a study in mice by Ernst et al. provides new insight into the role of IL-11 and its glycoprotein 130 (gp130) receptor in inflammation-associated gastric epithelial cell oncogenic transformation, which they show is mediated by and dependent on increased activation of Stat3 and, to a lesser extent, Stat1 (see the related article beginning on page 1727). Prior studies from this group have shown that Stat3 hyperactivity stimulates the TGF-[beta] inhibitor Smad7. Collectively, the studies suggest that an important pathway of oncogenic transformation in the stomach is through suppression of growth inhibitory signals, such as members of the TGF-[beta] family, that originate from the stroma., Cancer originates in a variety of different tissues that are susceptible to chronic inflammatory conditions. In the stomach, the phenotypic steps leading from chronic inflammation (gastritis) to distal gastric cancer [...]

Byline: Michael J. O'Dwyer (1,2), Arun K. Mankan (2), Mary White (1), Mathew W. Lawless (2), Patrick Stordeur (3), Brian O'Connell (4), Dermot P. Kelleher (2), Ross McManus (2), Thomas Ryan (1) Keywords: Sepsis syndrome; Cytokines; Reverse transcriptase polymerase chain reaction; Helper T-cells Abstract: Objective The development and progression of severe sepsis is related to a deficiency in pro-inflammatory cytokine production, characterised by lesser IFNI3 levels, which are not explained by variations in levels of the main putative regulator of IFNI3, namely IL-12. As alternative regulators of IFNI3 may be of greater importance in human sepsis, we investigated the hypothesis that the development of severe sepsis is related to variations in IL-18, IL-23 and IL-27 gene expression. Design and setting A prospective observational trial in a mixed intensive care unit (ICU) and hospital wards in a university teaching hospital. Patients and participants Sixty-two ICU patients with severe sepsis, 13 bacteraemic patients with no acute critical illness, and 10 healthy controls. Measurements and results All subjects were assayed for IL-18, IL-23 and IL-27 mRNA levels in peripheral blood. IL-27 mRNA levels distinguished between the three groups, with levels highest in the ICU group, intermediate in the bacteraemic group and lowest in the control group. IL-23 distinguished between the groups, with levels lowest in the ICU group. In late sepsis IL-23 and TNF[alpha] mRNA levels were directly related. IL-18 mRNA levels did not distinguish between the patient groups. Conclusions We conclude that the deficient pro-inflammatory response in patients with sepsis is expansive and includes deficient IL-23 and excessive IL-27 gene expression. This provides further evidence that upregulation of a cytokine-based immune response is beneficial in sepsis. Author Affiliation: (1) Department of Anaesthesia, St James's Hospital, Dublin, Ireland (2) Department of Clinical Medicine, Trinity College, Dublin, Ireland (3) Department of Immunology-Haematology-Transfusion, Hopital Erasme, Universite Libre de Bruxelles, Brussels, Belgium (4) Department of Clinical Microbiology, St James's Hospital, Dublin, Ireland Article History: Registration Date: 27/11/2007 Received Date: 15/08/2007 Accepted Date: 25/11/2007 Online Date: 29/01/2008 Article note: Electronic supplementary material The online version of this article (doi: 10.1007/s00134-007-0968-5) contains supplementary material, which is available to authorized users. Dr. Ryan and Dr. McManus are joint senior authors.

Objectives: To assess the effect of two similar olive oils, but with differences in their phenolic compounds (powerful antioxidant compounds), on inflammatory markers in stable coronary heart disease patients. Design: [...]

Objective: Pathophysiological processes in the first days after trauma seem to be important for the development and final outcome in cases of multiple organ failure (MOF). Our objective in this [...]

Interleukin (IL)-32 is a recently described proinflammatory cytokine, characterized by the induction of nuclear factor (NF)-[kappa]B activation. We studied IL-32[alpha] expression in human pancreatic periacinar myofibroblasts, which play important roles in the regulation of extracellular matrix metabolism and inflammatory responses in the pancreas. IL-32[alpha] protein expression was evaluated by Western blot analyses, and IL-32[alpha] mRNA expression was analyzed by Northern blot and real-time PCR analyses. IL-32[alpha] mRNA was weakly expressed without a stimulus, and its expression was markedly enhanced by IL-1[beta], IFN-[gamma], and TNF-[alpha]. 1[beta], IFN-[gamma], and TNF-[alpha] enhanced intracellular accumulation of IL-32[alpha] protein, but IL-32[alpha] was not detected in supernatants. Each cytokine dose and time dependently induced IL-32[alpha] mRNA expression. An inhibitor of phosphatidylinositol 3-kinase (LY294002) significantly suppressed IL-1[beta]-, IFN-[gamma]-, and TNF-[alpha]-induced IL-32[alpha] mRNA expression, although MAPK inhibitors had no effect. Akt activation in response to these cytokines was confirmed by Western blot. Furthermore, LY294002 suppressed both IL-1[beta]- and TNF-[alpha]-induced NF-[kappa]B activation and IL-1[beta]-, TNF-[alpha]-, and IFN-[gamma]-induced activated protein-1 (AP-1) activation. Blockade of NF-[kappa]B and AP-1 activation by an adenovirus expressing a stable mutant form of I[kappa]B[alpha] and a dominant negative mutant of c-Jun markedly suppressed IL-1[beta]-, IFN-[gamma]-, and/or TNF-[alpha]-induced IL-32[alpha] mRNA expression. Human pancreatic periacinar myofibroblasts expressed IL-32[alpha] in response to IL-1[beta], TNF-[alpha], and IFN-[gamma]. IL-32[alpha] mRNA expression is dependent on interactions between the phosphatidylinositol 3-kinase/Akt-pathway and the NF-[kappa]B/AP-1 system. pancreatitis; inflammation; cytokine

Psoriasis is a chronic skin disease resulting from the dysregulated interplay between keratinocytes and infiltrating immune cells. We report on a psoriasis-like disease model, which is induced by the transfer of [CD4.sup.+][CD45RB.sup.hi][CD25.sup.-] cells to pathogen-free scid/scid mice. Psoriasis-like lesions had elevated levels of antimicrobial peptide and proinflammatory cytokine mRNA. Also, similar to psoriasis, disease progression in this model was dependent on the p40 common to IL-12 and IL-23. To investigate the role of IL-22, a Th17 cytokine, in disease progression, mice were treated with IL-22-neutralizing antibodies. Neutralization of IL-22 prevented the development of disease, reducing acanthosis (thickening of the skin), inflammatory infiltrates, and expression of Th17 cytokines. Direct administration of IL-22 into the skin of normal mice induced both antimicrobial peptide and proinflammatory cytokine gene expression. Our data suggest that IL-22, which acts on keratinocytes and other nonhematopoietic cells, is required for development of the autoreactive Th17 cell--dependent disease in this model of skin inflammation. We propose that IL-22 antagonism might be a promising therapy for the treatment of human psoriasis., Introduction Psoriasis is a common, chronic autoimmune disease of the skin, which affects approximately 2% of the general population. The lesions are characterized by red, scaly, raised plaques at different [...]

Expression of IL-22 is induced in several human inflammatory conditions, including inflammatory bowel disease (IBD). Expression of the IL-22 receptor is restricted to innate immune cells; however, the role of IL-22 in colitis has not yet been defined. We developed what we believe to be a novel microinjection-based local gene-delivery system that is capable of targeting the inflamed intestine. Using this approach, we demonstrated a therapeutic potency for IL-22-mediated activation of the innate immune pathway in a mouse model of Th2-mediated colitis that induces disease with characteristics similar to that of IBD ulcerative colitis (UC). IL-22 gene delivery enhanced STAT3 activation specifically within colonic epithelial cells and induced both STAT3-dependent expression of mucus-associated molecules and restitution of mucus-producing goblet cells. Importantly, IL-22 gene delivery led to rapid amelioration of local intestinal inflammation. The amelioration of disease by IL-22 was mediated by enhanced mucus production. In addition, local gene delivery was used to inhibit IL-22 activity through overexpression of IL-22-binding protein. Treatment with IL-22-binding protein suppressed goblet cell restitution during the recovery phase of a dextran sulfate sodium--induced model of acute colitis. These data demonstrate what we believe to be a novel function for IL-22 in the intestine and suggest the potency of a local IL-22 gene--delivery system for treating UC., Introduction IL-22 belongs to the IL-10 family of cytokines (1-3) and has recently been shown to be preferentially expressed by the Th17 subset (4), (5). IL-22 targets innate immune pathways [...]

Matrix metalloproteinases (MMPs) degrade collagen and mediate tissue remodeling. The novel cytokine IL-17 is expressed during various inflammatory conditions and modulates MMP expression. We investigated the effect of IL-17 on MMP-1 expression in primary human cardiac fibroblasts (HCF) and delineated the signaling pathways involved. HCF were treated with recombinant human IL-17. MMP-1 expression was analyzed by Northern blotting, RT-quantitative PCR, Western blotting, and ELISA; transcriptional induction and transcription factor binding by EMSA, ELISA, and reporter assay; and p38 MAPK and ERK1/2 activation by protein kinase assays and Western blotting. Signal transduction pathways were investigated using pharmacological inhibitors, small interfering RNA (siRNA), and adenoviral dominant-negative expression vectors. IL-17 stimulated MMP-1 gene transcription, net mRNA levels, protein, and promoter-reporter activity in HCF. This response was blocked by IL-17 receptor-Fc chimera and IL-17 receptor antibodies, but not by IL-6, TNF-[alpha] or IL-1[beta] antibodies. IL-17-stimulated type I collagenase activity was inhibited by the MMP inhibitor GM-6001 and by siRNA-mediated MMP-1 knockdown. IL-17 stimulated activator protein-1 [AP-1 (c-Fos, c-Jun, and Fra-1)], NF-[kappa]B (p50 and p65), and CCAAT enhancer-binding protein (C/EBP)-[beta] DNA binding and reporter gene activities, effects attenuated by antisense oligonucleotides, siRNA-mediated knockdown, or expression of dominant-negative signaling proteins. Inhibition of AP-1, NF-[kappa]B, or C/EBP activation attenuated IL-17-stimulated MMP-1 expression. IL-17 induced p38 MAPK and ERK1/2 activation, and inhibition by SB-203580 and PD-98059 blunted IL-17-mediated transcription factor activation and MMP-1 expression. Our data indicate that IL-17 induces MMP-1 in human cardiac fibroblasts directly via p38 MAPK-and ERK-dependent AP-1, NF-[kappa]B, and C/EBP-[beta] activation and suggest that IL-17 may play a critical role in myocardial remodeling. cytokines; interleukins; matrix metalloproteinases; fibrosis

Development of persistent Th2 responses in asthma and chronic helminth infections are a major health concern. IL-10 has been identified as a critical regulator of Th2 immunity, but mechanisms for [...]

T cell-mediated autoimmune diseases such as multiple sclerosis and rheumatoid arthritis are driven by autoaggressive Th cells. The pathogenicity of such Th cells has, in the past, been considered to [...]