Cytokine/chemokine transcript profiles reflect mucosal inflammation in Crohn?s disease

Stallmach, Andreas; Giese, Thomas; Schmidt, Carsten; Ludwig, Bjoern; Mueller-Molaian, Ina; Meuer, Stefan

doi:10.1007/s00384-003-0554-4

Cited by 101 publications

(64 citation statements)

References 25 publications

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“…Increases in p19 expression were reported in intestinal mucosal biopsies from CrD and UC patients, but not in non-IBD colitis patients (58,59), and a nonsynonymous variant of the IL-23R has been reported as one of the three markers associated with childhood onset of IBD (the other two markers being located in the NOD2/CARD15 gene) (60). In a model of spontaneous colitis, p19-deficient mice were shown to be disease resistant, and IL-23 administration together with transfer of CD4 ϩ CD45RB high T cells into Rag-1-deficient mice significantly accelerated disease onset (19).…”

Section: Discussionmentioning

confidence: 99%

The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23→IL-17 Axis

Sheibanie

Yen

Khayrullina

et al. 2007

The Journal of Immunology

253

196

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Although Crohn’s disease has been traditionally considered to be Th1-mediated, the newly identified Th17 cells emerged recently as crucial participants. Th1/Th17 differentiation is controlled primarily by the IL-12 family of cytokines secreted by activated dendritic cells (DCs) and macrophages. IL-23 and IL-12/IL-27 have opposite effects, supporting the Th17 and Th1 phenotypes, respectively. We found that PGE2, a major lipid mediator released in inflammatory conditions, shifts the IL-12/IL-23 balance in DCs in favor of IL-23, and propose that high levels of PGE2 exacerbate the inflammatory process in inflammatory bowel disease through the IL-23→IL-17 axis. We assessed the effects of PGE2 on IL-12, IL-27, and IL-23 and found that PGE2 promotes IL-23, inhibits IL-12 and IL-27 expression and release from stimulated DCs, and subsequently induces IL-17 production in activated T cells. The effects of PGE2 are mediated through the EP2/EP4 receptors on DCs. In vivo, we assessed the effects of PGE analogs in an experimental model for inflammatory bowel disease and found that the exacerbation of clinical symptoms and histopathology correlated with an increase in IL-23 and IL-17, a decrease in IL-12p35 expression in colon and mesenteric lymph nodes, and a substantial increase in the number of infiltrating neutrophils and of CD4+IL-17+ T cells in the colonic tissue. These studies suggest that high levels of PGE2 exacerbate the inflammatory process through the preferential expression and release of DC-derived IL-23 and the subsequent support of the autoreactive/inflammatory Th17 phenotype.

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Section: Discussionmentioning

confidence: 99%

The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23→IL-17 Axis

Sheibanie

Yen

Khayrullina

et al. 2007

The Journal of Immunology

253

196

View full text Add to dashboard Cite

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“…Interestingly, IL-23p19 mRNA levels are increased in experimental colitis 49 and in Crohn disease patients. 50 Moreover, mice overexpressing IL-23p19 develop multiple organ failure and systemic inflammation and die before 3 months of age. 51 Since LPS-induced IL-12p40 gene expression is reduced by Ad5STAT3C, the decreased production of this subunit may not only impair IL-12 secretion but also reduce the production of IL-23 in BMDCs.…”

Section: Discussionmentioning

confidence: 99%

STAT3 regulates NF-κB recruitment to the IL-12p40 promoter in dendritic cells

Hoentjen

Sartor

Ozaki

et al. 2005

Blood

134

111

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Interleukin-10-deficient (IL-10 IntroductionInterleukin-10-deficient (IL-10 Ϫ/Ϫ ) mice develop spontaneous T-helper 1 (Th-1)-mediated colitis when housed under specific pathogen-free (SPF) conditions. [1][2][3] In this experimental model, enhanced IL-12p40 production by immune cells represents a key feature of intestinal inflammation, as demonstrated by the prevention and partial treatment of colitis by anti-IL-12 antibodies. 4,5 This suggests that in absence of IL-10, the host mounts a dysregulated innate response to the commensal intestinal microflora. Dendritic cells (DCs) are at the interface of innate and adaptive immunity by virtue of their ability to secrete various cytokines including tumor necrosis factor ␣ (TNF␣), 7 For instance, IL-12p40-producing DCs skewed T-cell differentiation toward a Th-1 profile, a hallmark in the IL-10 Ϫ/Ϫ experimental mouse model. 8,9 However, the molecular mechanisms of dysregulated IL-12p40 gene expression in IL-10 Ϫ/Ϫ mice following SPF transfer are still poorly understood.IL-10 is a potent immunoregulatory cytokine with numerous effects, such as down-regulation of proinflammatory cytokines, chemokines, and costimulatory molecules. 10 Several mechanisms have been proposed for the IL-10-mediated inhibition of lipopolysaccharide (LPS)-induced proinflammatory gene expression, including activation of the heme oxygenase (HO)/carbon monoxide pathway, 11 inhibition of the nuclear factor-B (NF-B) pathway 12-14 and mitogen-activated protein (MAP) kinase activity, 15 mRNA stability, 16 signal transducers and activators of transcription 3 (STAT3) activation, 17 and induction of B-cell/lymphoma 3 (Bcl3). 18 However, the molecular mechanisms for dysregulated host innate responses in the IL-10 Ϫ/Ϫ mouse model are still unknown. IL-10 mediates its inhibitory effects through binding to its receptor complex, which induces activation of the cytoplasmic receptor-associated Janus kinase 1 (JAK1) and tyrosine kinase-2 (Tyk2). 10 This is followed by STAT3 phosphorylation, homodimerization, and translocation to the nucleus where it binds to STATbinding elements in the promoters of various IL-10-inducible genes, including suppressor of cytokine signaling 3 (SOCS3) and Bcl3. 10,18 The pivotal role of STAT3 in maintaining host homeostasis is clearly demonstrated by studies using genetic deletion. For example, STAT3 deletion is embryogenically lethal, 19 and myeloid cell-specific STAT3-deficient mice develop severe enterocolitis. 20 STAT3 deletion in bone marrow cells leads to overly activated innate immune responses 21 and interferes with the adaptive immune system by inhibiting the induction of antigen-specific T-cell tolerance. 22 Moreover, STAT3 gene inactivation leads to an aggressive and fatal form of enterocolitis mediated by These data highlight the pivotal role of STAT3 in controlling innate immunity. The absence of endogenous IL-10 in IL-10 Ϫ/Ϫ mice provides a powerful means to investigate the immunoregulatory mechanisms of this cytokine. To date, the Materials and methods Cell isolation...

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“…106,107 Mice lacking IRF2 are hyper-responsive to IFN-a/b, dramatically overexpress genes induced by type I IFN and develop inflammatory dermatological manifestations involving CD8 þ T cells. 108 Numerous lines of evidence suggest that pathways influenced by IFNs are dysregulated in multiple autoimmune diseases, including SLE, PS, AITD, Crohn's, RA and spondyloarthropathy, [109][110][111][112][113] supporting a potential role for genes such as IRF2.…”

mentioning

confidence: 99%

Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus

et al. 2006

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Autoantibodies are clinically relevant biomarkers for numerous autoimmune disorders. The genetic basis of autoantibody production in systemic lupus erythematosus (SLE) and other autoimmune diseases is poorly understood. In this study, we characterized autoantibody profiles in 1506 individuals from 229 multiplex SLE pedigrees. There was strong familial aggregation of antinuclear antibodies (ANAs), anti-double-stranded DNA (dsDNA), anti-La/SSB, anti-Ro/SSA, anti-Sm, antinRNP (nuclear ribonucleoprotein), IgM antiphospholipid (aPL) antibodies (Abs) and rheumatoid factor (RF) across these families enriched for lupus. We performed genome-wide linkage analyses in an effort to map genes that contribute to the production of the following autoantibodies: Ro/SSA, La/SSB, nRNP, Sm, dsDNA, RF, nuclear and phospholipids. Using an approach to minimize false positives and adjust for multiple comparisons, evidence for linkage was found to anti-La/SSB Abs on chromosome 3q21 (adjusted P ¼ 1.9 Â 10 À6 ), to anti-nRNP and/or anti-Sm Abs on chromosome 3q27 (adjusted P ¼ 3.5 Â 10 À6 ), to anti-Ro/SSA and/or anti-La/SSB Abs on chromosome 4q34-q35 (adjusted P ¼ 3.4 Â 10 À4 ) and to antiIgM aPL Abs on chromosome 13q14 (adjusted P ¼ 2.3 Â 10 À4). These results support the hypothesis that autoantibody production is a genetically complex trait. Identification of the causative alleles will advance our understanding of critical molecular mechanisms that underlie SLE and perhaps other autoimmune diseases.

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Cytokine/chemokine transcript profiles reflect mucosal inflammation in Crohn?s disease

Cited by 101 publications

References 25 publications

The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23→IL-17 Axis

The Proinflammatory Effect of Prostaglandin E2 in Experimental Inflammatory Bowel Disease Is Mediated through the IL-23→IL-17 Axis

STAT3 regulates NF-κB recruitment to the IL-12p40 promoter in dendritic cells

Familial aggregation and linkage analysis of autoantibody traits in pedigrees multiplex for systemic lupus erythematosus

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