The proportion of Th1 cells, which prevail in gut mucosa, is decreased in inflammatory bowel syndrome (original) (raw)
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Proinflammatory properties of IL-4 in the intestinal microenvironment
AJP: Gastrointestinal and Liver Physiology, 2005
IL-4 is involved in type 2 T helper cell (Th)2-type immune responses and, in some cases, can promote Th1 responses. However, the proinflammatory potential of IL-4 alone is unclear. In this study, we examined the ability of IL-4 to induce colitis after its overexpression in the colon using an adenoviral vector (Ad5) and compared results with those obtained after overexpression of IL-12, a cytokine implicated in several models of colitis. Overexpression of IL-4 or IL-12 caused a fatal colitis within 24 h in 60% of animals and was dose and strain dependent. IL-12-induced colitis was accompanied by the local expression of IFN-γ and TNF-α but not IL-4 mRNA and protein. Conversely, IL-4-induced colitis was accompanied by the local expression of IL-4 and TNF-α but not IFN-γ mRNA and protein. The Ad5-IL4-induced colitis did not persist beyond 3 days and was present in recombinase activation gene-2 (RAG-2)−/− mice but not in STAT6−/− mice. Acute lethal colitis induced by Ad5IL12 was T cell m...
Human Gene Therapy, 2000
Inflammatory bowel disease (IBD) comprises the two disorders ulcerative colitis (UC) and Crohn's disease (CD). Although the etiology is still unclear, initiation and aggravation of the inflammatory processes seem to be due to a massive local mucosal immune response. An increased number of greatly activated macrophages seems to contribute to the onset of IBD by expressing upregulated costimulatory molecules (e.g., CD80/CD86) and a cytokine profile favouring a type I proinflam matory response. The release of interleukin 2 (IL-2) and Interferon-c (IFN-c) by naive T lymphocytes predominantly stimulates cytotoxic T lymphocytes, macrophages, and natural killer (NK) cells and increases the antigen-presenting potential of all these cell types. Opposite this proinflammatory immune reaction a compensatory type II antiinflam matory response has been suggested in the inflamed mucosa, involving mainly interleukin 4 and interleukin 10. Both cytokines are able to downregulate inflammatory mediators including tumor necrosis factor-a (TNF-a) and interleukin 1 and favor a humoral immune response. The main goal of this clinical trial is the local liposom e-mediated gene transfer of these two antiinflam matory cytokines, interleukin 4 and interleukin 10, in patients with severe IBD of the rectum. This local administration of antiinflam matory cytokines will avoid toxic systemic side effects, prevents blocking of the beneficial effects of proinflam matory cytokines, e.g., TNF-a in other tissue compartments and increases the local concentration of interleukin 4 and interleukin 10 over a prolonged period of time. The combined effects of IL-4 and IL-10 have been shown to shift the Th1/Th2 cell activation in favor of a Th2 immune response which seems to be essential for fighting against the inflammation and ultimative healing.
Regulation of inflammation by interleukin-4: a review of "alternatives
Journal of Leukocyte Biology, 2012
Studies of IL-4 have revealed a wealth of information on the diverse roles of this cytokine in homeostatic regulation and disease pathogenesis. Recent data suggest that instead of simple linear regulatory pathways, IL-4 drives regulation that is full of alternatives. In addition to the well-known dichotomous regulation of Th cell differentiation by IL-4, this cytokine is engaged in several other alternative pathways. Its own production involves alternative mRNA splicing, yielding at least two functional isoforms: full-length IL-4, encoded by the IL-4 gene exons 1-4, and IL-4␦2, encoded by exons 1, 3, and 4. The functional effects of these two isoforms are in some ways similar but in other ways quite distinct. When binding to the surface of target cells, IL-4 may differentially engage two different types of receptors. By acting on macrophages, a cell type critically involved in inflammation, IL-4 induces the so-called alternative macrophage activation. In this review, recent advances in understanding these three IL-4-related branch points-alternative splicing of IL-4, differential receptor engagement by IL-4, and differential regulation of macrophage activation by IL-4 -are summarized in light of their contributions to inflammation. J. Leukoc. Biol. 92: 753-764; 2012.
…, 2006
Interleukin-12 (IL-12) and IL-4 are known to differentially promote T helper (Th) cell differentiation. While IL-12 induces interferon-c (IFN-c) production and maturation of Th1 cells, IL-4 is thought to antagonize IL-12 and to favour Th2 development. Here we studied the combined action of various concentrations of common c-chain (c c -chain) cytokines, including IL-4 and the Th1 cytokine IL-12, in human activated lymphoblasts and Th1 cells. IL-4 and IL-7 potentiated IL-12-induced proliferation at every concentration tested (1-10 ng/ml) without increasing rescue from apoptosis, indicating that proliferation was directly affected by these cytokine combinations. With regards to cytokine secretion, IL-2 together with IL-12 initiated tumour necrosis factor-a synthesis, enhanced IFN-c production, and shedding of soluble IL-2 receptor a as expected. Importantly, combining IL-4 with IL-12 also enhanced IFN-c secretion in lymphoblasts and a Th1 cell line. Investigating signal transduction in lymphoblasts induced by these cytokines, we found that not only IL-2 but also IL-4 enhances signal transducer and activator of transcription 3 (STAT3) tyrosine phosphorylation by IL-12. Tyrosine phosphorylations of janus kinase 2 (JAK-2), tyrosine kinase 2 (TYK2), extracellular signal-regulated kinase (ERK) and STAT4, STAT5 and STAT6 were not potentiated by combinations of these cytokines, suggesting specificity for increased STAT3 phosphorylation. In conclusion, two otherwise antagonizing cytokines co-operate in activated human lymphoblasts and Th1 cells, possibly via STAT3 as a converging signal. These data demonstrate that IL-4 can directly enhance human Th1 cell function independently of its known actions on antigen-presenting cells. These findings should be of importance for the design of cytokine-targeted therapies of human Th-cell-driven diseases.
Immunology, 1999
Interleukin-4 (IL-4) is the prototypic type 2 immunoregulatory cytokine that can suppress the production of many monocyte and macrophage pro-inflammatory mediators. In this study we investigated the regulation by IL-4 of IL-12 and IL-10 production. While IL-4 suppressed lipopolysaccharide (LPS)-induced IL-12 and IL-10 production by human peripheral blood monocytes, IL-4 suppressed LPS-induced IL-12, but not IL-10, production by synovial fluid mononuclear cells from patients with rheumatoid arthritis. IL-4 also suppressed IL-12, but not IL-10 production, by LPS-stimulated in vitro monocyte-derived macrophages. Similarly, IL-4 cannot suppress LPS-induced tumour necrosis factor-a (TNF-a) production by synovial fluid cells and monocyte-derived macrophages. The failure of IL-4 to regulate IL-10 production is not due to the failure of IL-4 to suppress TNF-a, and vice versa. The data suggest that the IL-4 receptor subunit, c c , is essential for IL-4 regulation of LPS-induced IL-10 production and that a correlation exists between duration of monocyte culture, reduction in c c mRNA in cultured cells and hyporesponsiveness of monocyte-derived macrophages to IL-4 for regulation of LPS-induced IL-10 production. This study highlights the importance of investigating responses to IL-4, as a potential therapeutic anti-inflammatory agent, by cells isolated from inflammatory sites and not by the more easily accessible blood monocytes. This study emphasizes the involvement of signalling from c c in IL-4 regulation of LPS-induced IL-10 production by monocytes and macrophages.
Journal of Biomedical Science, 1999
The immune responses of the intestine mucosa feature the noninflammatory type, such as lgA production and oral tolerance, Th2 type cytokines have been implicated in the induction of these noninflammatory responses. In the present study, cytokine responses of CD8+ and CD4+ TCR(zl3+ intestinal intraepithelial lymphocyte (a13 ilEL) subsets to TCR stimulation under the influence of IL-12, IL-4, or CD28 costimulation were examined. IL-12 enhanced production of IL-10 and IFN-,/by the CD8al3+ ap ilEL significantly but only marginally affected the CD8aa+ subset, whereas IL-4 induced IL-4, IL-5, and IL-10 production and augmented TGF-I3 production by both subsets. CD28 costimulation induced production of Th2 cytokines by CD4+ ilEL in the absence of exogenous IL-4. Unlike lymph node CD4+ cells, the CD28 costimulation-induced Th2 differentiation of CD4+ ilEL was not inhibited by IFN-,/. These results demonstrate active cytokine production by CD4+, CD8{zl3+, as well as CD8~a+ 0~13 ilEL. The Th2-skewed cytokine profile of CD8(za+ o~p ilEL and the IFN-,/-resistance of Th2 differentiation of the CD4+ a13 ilEL suggest that both ilEL subsets contribute to the induction of noninflammatory mucosal immune responses.
CD4+ T cell mediated intestinal immunity: chronic inflammation versus immune regulation
Gut, 2005
Background: Several studies have suggested that chronic inflammatory bowel disease may be a consequence of antigen specific recognition by appropriate T cells which expand and induce immunopathology. Aims: We wished to investigate whether autoreactive CD4 + T cells can initiate the disease on recognition of enterocyte specific antigens directly and if induction of mucosal tolerance occurs. Methods: Transgenic mice (VILLIN-HA) were generated that showed specific expression of haemagglutinin from influenza virus A exclusively in enterocytes of the intestinal epithelium. To investigate the impact of enterocyte specific haemagglutinin expression in an autoimmune environment, we mated VILLIN-HA mice with T cell receptor (TCR)-HA mice expressing an a/b-TCR, which recognises an MHC class II restricted epitope of haemagglutinin, and analysed the HA specific T cells for induction of autoimmunity or tolerance. Results: In VILLIN-HA6TCR-HA mice, incomplete central deletion of HA specific lymphocytes occurred. Peripheral HA specific lymphocytes showed an activated phenotype and increased infiltration into the intestinal mucosa, but not into other organs of double transgenic mice. Enterocyte specific lamina propria lymphocytes showed a dose dependent proliferative response on antigen stimulation whereas the proliferative capacity of intraepithelial lymphocytes was reduced. Mucosal lymphocytes from VILLIN-HA6TCR-HA mice secreted lower amounts of interferon c and interleukin (IL)-2 but higher levels of tumour necrosis factor a, monocyte chemoattractant protein 1, and IL-6. Mucosal immune reactions were accompanied by broad changes in the gene expression profile with expression of proinflammatory genes, but strikingly also a remarkable set of genes discussed in the context of peripheral induction of regulatory T cells, including IL-10, Nrp-1, and Foxp3. Conclusions: Enterocyte specific antigen expression is sufficient to trigger a specific CD4 + T cell response leading to mucosal infiltration. In our model, progression to overt clinical disease was counteracted most likely by induction of regulatory T cells.
Clinical and Experimental Immunology, 1999
To investigate the role of IFN-g in the immunopathogenesis of inflammatory bowel disease (IBD), severe combined immunodeficient (SCID) mice were transplanted with in vitro activated CD4 þ T cells from either wild-type (WT) or IFN-g-deficient (IFN-gKO) BALB/c mice. In vitro, the two types of T cells displayed comparable proliferation rates and production of tumour necrosis factor-alpha (TNF-a), IL-2, IL-4 and IL-10 after concanavalin A (Con A) stimulation. When transplanted into SCID mice, WT CD4 þ blasts induced a lethal IBD, whereas IFN-gKO blasts induced a less severe intestinal inflammation with moderate weight loss. Intracellular cytokine staining of lamina propria lymphocytes (LPL) revealed comparable fractions of CD4 þ T cells positive for TNF-a, IL-2 and IL-10 in the two groups of transplanted SCID mice, whereas a two-to-three-fold increase in the fraction of IL-4-positive cells was found in IFN-gKO-transplanted SCID mice. Flow cytometric analyses showed strong up-regulation of MHC class II expression of colonic epithelial cells of WT-CD4 þ T cell-transplanted compared with IFN-gKO-transplanted SCID mice. A significantly higher fraction of CD4 þ LPL were found to enter the cell cycle, i.e. to incorporate bromo-dexoy-uridine, and to undergo apoptosis in vivo in WT-transplanted compared with IFN-gKO-transplanted SCID mice. These data point towards an important role for IFN-g in the development of IBD in SCID mice. The inflammation might be initiated and subsequently enhanced by the ability of IFN-g to induce de novo MHC class II expression in the colonic epithelium, a change which could lead to increased antigen processing and production of local proinflammatory cytokines, CD4 þ T cell turnover and thereby to exaggeration of disease.