FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2167264906> ?p ?o ?g. }

• W2167264906 endingPage "318" @default.
• W2167264906 startingPage "309" @default.
• W2167264906 abstract "The CD40-CD154 pathway is important in the pathogenesis of inflammatory bowel disease. Here we show that injection of an agonistic CD40 mAb to T and B cell-deficient mice was sufficient to induce a pathogenic systemic and intestinal innate inflammatory response that was functionally dependent on tumor necrosis factor-α and interferon-γ as well as interleukin-12 p40 and interleukin-23 p40 secretion. CD40-induced colitis, but not wasting disease or serum proinflammatory cytokine production, depended on interleukin-23 p19 secretion, whereas interleukin-12 p35 secretion controlled wasting disease and serum cytokine production but not mucosal immunopathology. Intestinal inflammation was associated with IL-23 (p19) mRNA-producing intestinal dendritic cells and IL-17A mRNA within the intestine. Our experiments identified IL-23 as an effector cytokine within the innate intestinal immune system. The differential role of IL-23 in local but not systemic inflammation suggests that it may make a more specific target for the treatment of IBD. The CD40-CD154 pathway is important in the pathogenesis of inflammatory bowel disease. Here we show that injection of an agonistic CD40 mAb to T and B cell-deficient mice was sufficient to induce a pathogenic systemic and intestinal innate inflammatory response that was functionally dependent on tumor necrosis factor-α and interferon-γ as well as interleukin-12 p40 and interleukin-23 p40 secretion. CD40-induced colitis, but not wasting disease or serum proinflammatory cytokine production, depended on interleukin-23 p19 secretion, whereas interleukin-12 p35 secretion controlled wasting disease and serum cytokine production but not mucosal immunopathology. Intestinal inflammation was associated with IL-23 (p19) mRNA-producing intestinal dendritic cells and IL-17A mRNA within the intestine. Our experiments identified IL-23 as an effector cytokine within the innate intestinal immune system. The differential role of IL-23 in local but not systemic inflammation suggests that it may make a more specific target for the treatment of IBD. The inflammatory bowel diseases (IBD) encompassing Crohn's disease (CD) and ulcerative colitis are chronic inflammatory disorders of the gastrointestinal tract that affect approximately 0.1% of Western populations (Bouma and Strober, 2003Bouma G. Strober W. The immunological and genetic basis of inflammatory bowel disease.Nat. Rev. Immunol. 2003; 3: 521-533Crossref PubMed Scopus (1410) Google Scholar, Shanahan, 2002Shanahan F. Crohn's disease.Lancet. 2002; 359: 62-69Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar). Available evidence suggests that IBD involves an aberrant inflammatory response to intestinal bacteria in genetically susceptible individuals. The immune pathogenesis of CD is associated with increased inflammatory cytokines including tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and interleukin-12 and interleukin-23 p40 (IL-12p40, IL-23p40). Accordingly, anti-TNF-α therapy has been shown to be beneficial in CD patients (Sandborn and Faubion, 2004Sandborn W.J. Faubion W.A. Biologics in inflammatory bowel disease: how much progress have we made?.Gut. 2004; 53: 1366-1373Crossref PubMed Scopus (54) Google Scholar). However, a limitation of this approach is that TNF-α also plays a pivotal role in protection from infection. Indeed, sustained blockade of TNF-α has been reported to increase susceptibility to infection such as reactivation of Mycobacterium tuberculosis (Sandborn and Faubion, 2004Sandborn W.J. Faubion W.A. Biologics in inflammatory bowel disease: how much progress have we made?.Gut. 2004; 53: 1366-1373Crossref PubMed Scopus (54) Google Scholar). These findings highlight the need to develop more specific strategies that discriminate the local pathogenic inflammatory response from systemic host protective immunity. Interactions between CD40 and CD154 (CD40L) are important in the initiation and maintenance of T cell-mediated intestinal inflammation. In the inflamed intestinal tissue of human IBD patients, as well as in mouse models of IBD, CD40+ antigen-presenting cells (APC) are found in association with CD40L+ T cells (Liu et al., 1999Liu Z. Colpaert S. D'Haens G.R. Kasran A. de Boer M. Rutgeerts P. Geboes K. Ceuppens J.L. Hyperexpression of CD40 ligand (CD154) in inflammatory bowel disease and its contribution to pathogenic cytokine production.J. Immunol. 1999; 163: 4049-4057PubMed Google Scholar, Liu et al., 2000Liu Z. Geboes K. Colpaert S. Overbergh L. Mathieu C. Heremans H. de Boer M. Boon L. D'Haens G. Rutgeerts P. Ceuppens J.L. Prevention of experimental colitis in SCID mice reconstituted with CD45RBhigh CD4+ T cells by blocking the CD40-CD154 interactions.J. Immunol. 2000; 164: 6005-6014PubMed Google Scholar, Polese et al., 2002Polese L. Angriman I. Cecchetto A. Norberto L. Scarpa M. Ruffolo C. Barollo M. Sommariva A. D'Amico D.F. The role of CD40 in ulcerative colitis: histochemical analysis and clinical correlation.Eur. J. Gastroenterol. Hepatol. 2002; 14: 237-241Crossref PubMed Scopus (34) Google Scholar). Importantly, blockade of CD40-CD40L interactions inhibits the development of colitis and can ameliorate established disease in mouse models (Cong et al., 2000Cong Y. Weaver C.T. Lazenby A. Elson C.O. Colitis induced by enteric bacterial antigen-specific CD4+ T cells requires CD40-CD40 ligand interactions for a sustained increase in mucosal IL-12.J. Immunol. 2000; 165: 2173-2182Crossref PubMed Scopus (78) Google Scholar, De Jong et al., 2000De Jong Y.P. Comiskey M. Kalled S.L. Mizoguchi E. Flavell R.A. Bhan A.K. Terhorst C. Chronic murine colitis is dependent on the CD154/CD40 pathway and can be attenuated by anti-CD154 administration.Gastroenterology. 2000; 119: 715-723Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, Kelsall et al., 1996Kelsall B.L. Stuber E. Neurath M. Strober W. Interleukin-12 production by dendritic cells. The role of CD40-CD40L interactions in Th1 T-cell responses.Ann. N Y Acad. Sci. 1996; 795: 116-126Crossref PubMed Scopus (126) Google Scholar, Liu et al., 2000Liu Z. Geboes K. Colpaert S. Overbergh L. Mathieu C. Heremans H. de Boer M. Boon L. D'Haens G. Rutgeerts P. Ceuppens J.L. Prevention of experimental colitis in SCID mice reconstituted with CD45RBhigh CD4+ T cells by blocking the CD40-CD154 interactions.J. Immunol. 2000; 164: 6005-6014PubMed Google Scholar). These results suggest that after antigen encounter, activated CD4+CD40L+ T cells stimulate CD40+ APC via the CD40L-CD40 pathway. This in turn leads to further activation of APC and T cells, establishing a positive feedback loop of immune activation (Diehl et al., 2000Diehl L. Den Boer A.T. van der Voort E.I. Melief C.J. Offringa R. Toes R.E. The role of CD40 in peripheral T cell tolerance and immunity.J. Mol. Med. 2000; 78: 363-371Crossref PubMed Scopus (61) Google Scholar, van Kooten and Banchereau, 2000van Kooten C. Banchereau J. CD40-CD40 ligand.J. Leukoc. Biol. 2000; 67: 2-17Crossref PubMed Scopus (1115) Google Scholar). In this type of inflammatory cascade, both CD4+ T cells and APC can contribute to immunopathology with effector mechanisms including cytokine production (Strober et al., 2002Strober W. Fuss I.J. Blumberg R.S. The immunology of mucosal models of inflammation.Annu. Rev. Immunol. 2002; 20: 495-549Crossref PubMed Scopus (1105) Google Scholar). CD40 stimulation of myeloid cells can lead to IL-12 production (Stuber et al., 1996Stuber E. Strober W. Neurath M. Blocking the CD40L-CD40 interaction in vivo specifically prevents the priming of T helper 1 cells through the inhibition of interleukin 12 secretion.J. Exp. Med. 1996; 183: 693-698Crossref PubMed Scopus (317) Google Scholar). This cytokine plays a key role in the inflammatory response primarily due to its ability to induce IFN-γ production by T cells and NK cells (Trinchieri et al., 2003Trinchieri G. Pflanz S. Kastelein R.A. The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses.Immunity. 2003; 19: 641-644Abstract Full Text Full Text PDF PubMed Scopus (757) Google Scholar). In intestinal inflammation, administration of neutralizing IL-12p40 mAbs ameliorates colitis in several different models (Neurath et al., 1996Neurath M.F. Fuss I. Kelsall B. Meyer zum Buschenfelde K.H. Strober W. Effect of IL-12 and antibodies to IL-12 on established granulomatous colitis in mice.Ann. N Y Acad. Sci. 1996; 795: 368-370Crossref PubMed Scopus (28) Google Scholar, Simpson et al., 1998Simpson S.J. Shah S. Comiskey M. de Jong Y.P. Wang B. Mizoguchi E. Bhan A.K. Terhorst C. T cell-mediated pathology in two models of experimental colitis depends predominantly on the interleukin 12/Signal transducer and activator of transcription (Stat)-4 pathway, but is not conditional on interferon gamma expression by T cells.J. Exp. Med. 1998; 187: 1225-1234Crossref PubMed Scopus (240) Google Scholar). This therapeutic effect is linked to reductions in IL-12-driven IFN-γ secretion as well as the induction of Fas-mediated apoptosis of Th1 cells (Fuss et al., 1999Fuss I.J. Marth T. Neurath M.F. Pearlstein G.R. Jain A. Strober W. Anti-interleukin 12 treatment regulates apoptosis of Th1 T cells in experimental colitis in mice.Gastroenterology. 1999; 117: 1078-1088Abstract Full Text Full Text PDF PubMed Scopus (234) Google Scholar). In a recent study, anti-IL-12p40 treatment in CD led to an amelioration of inflammation in some patients (Mannon et al., 2004Mannon P.J. Fuss I.J. Mayer L. Elson C.O. Sandborn W.J. Present D. Dolin B. Goodman N. Groden C. Hornung R.L. et al.Anti-interleukin-12 antibody for active Crohn's disease.N. Engl. J. Med. 2004; 351: 2069-2079Crossref PubMed Scopus (724) Google Scholar). Clinical improvement was associated with a reduction in the production of IL-12 and IFN-γ by mononuclear cells from the intestine. However, it is now known that IL-12p40 forms heterodimers not only with IL-12p35 (IL-12p35p40; IL-12p70) but also with IL-23p19 (IL-23p19p40). These results raise the possibility that activities previously ascribed to IL-12 may in fact be attributable to IL-23. Indeed, the immune pathological response in experimental autoimmune encephalomyelitis (Cua et al., 2003Cua D.J. Sherlock J. Chen Y. Murphy C.A. Joyce B. Seymour B. Lucian L. To W. Kwan S. Churakova T. et al.Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.Nature. 2003; 421: 744-748Crossref PubMed Scopus (2245) Google Scholar) and collagen-induced arthritis (Murphy et al., 2003Murphy C.A. Langrish C.L. Chen Y. Blumenschein W. McClanahan T. Kastelein R.A. Sedgwick J.D. Cua D.J. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation.J. Exp. Med. 2003; 198: 1951-1957Crossref PubMed Scopus (1334) Google Scholar) has been shown to be functionally dependent on IL-23 and not IL-12. To assess the role of CD40-mediated effector function in the innate response and to further probe the role of IL-12 and IL-23 in this pathway, we injected T and B cell-deficient mice with an agonistic CD40 mAb. Anti-CD40 stimulation led to a systemic and local inflammatory disease characterised by wasting disease, splenomegaly, increases in serum inflammatory cytokines, and colitis. Functional analysis showed that the systemic inflammatory response was driven by IL-12 and not IL-23, whereas local intestinal inflammation required the presence of IL-23 and was independent of IL-12. These results newly identify IL-23 as a key effector cytokine within the innate intestinal immune system and point to divergent roles for IL-12 and IL-23 in local and systemic inflammation. To assess the effects of CD40 stimulation on the activation of the innate immune system, we injected immunodeficient recombinase-activating gene 1-deficient (Rag1 KO) mice with 200 μg CD40 mAb. Clinically, the mice developed wasting disease as well as gastrointestinal symptoms including diarrhea and anal inflammation. CD40 mAb-treated Rag1 KO mice developed rapid weight loss, up to 20% within the first 4 days (Figure 1A). 7 days after antibody challenge, the weight was still substantially decreased compared to isotype- or PBS-treated control mice. At this time, all CD40 mAb-treated mice developed splenomegaly. Other pathological changes in these mice included hepatopathy, lymphadenomegaly of the mesenteric lymph node (MLN), and colon pathology, as indicated by swelling of the colon wall and presence of edema. 10 days after CD40 stimulation, the mice recovered clinically but still showed macroscopical signs of colon pathology, whereas 3 weeks after the initiation of the immune response, no pathology was observed (data not shown). None of these changes were seen when two different isotype control antibodies or PBS injections were used. C.B-17 SCID mice developed similar pathology after anti-CD40 stimulation (data not shown). Consistent with macroscopic observations, 7 days after CD40 mAb challenge, mice had histological signs of colitis with pronounced epithelial hyperplasia and marked leukocyte infiltration within the lamina propria, goblet cell depletion, and epithelial cell destruction (Figures 1B and 1C and Figures S1A–S1C in the Supplemental Data available with this article online). 10 days after CD40 activation, there was still marked leucocytic infiltration, but by 3 weeks after CD40 stimulation, all histological changes had resolved (data not shown). In summary, our results indicate that CD40 mAb treatment in immunodeficient mice induces weight loss and intestinal pathology. In line with the pathological and histopathological observations, marked increases in total leukocytes were found in the spleen and locally in the colon in anti-CD40-treated mice (Figure S1C). CD40 is abundantly expressed on CD11chi dendritic cells (DCs) of SCID or Rag1 KO mice (Figure 2A), and these cells became activated with increases in MHC-II, CD80, and CD86 expression at early time points after anti-CD40 stimulation (Figure 2A). There was also a marked increase in the density of CD11chi DC in leucocytic clusters in the colon (Figure 2B). Changes in serum cytokines and chemokines were analyzed to determine whether these correlate with the development of anti-CD40-induced disease. Serum was assayed at day 3, when the anti-CD40-stimulated mice had their maximum weight loss and the first signs of colon pathology, as well as at day 7, when intestinal pathology peaked. Increased amounts of TNF-α, IL-6, IFN-γ, MCP-1, and IL-12p70 were found in CD40 mAb-treated mice. There was no significant change in IL-10 (Figure 2C). Anti-CD40 treatment induced comparable local and systemic immune pathology in germ-free and specific pathogen-free (SPF) housed animals, suggesting that the CD40-mediated activation pathway is not dependent on the preactivation of the innate immune system by replicating resident bacteria (Supplemental Data and Figure S2). To test whether proinflammatory cytokines played a functional role in the development of the anti-CD40-mediated immunopathology, Rag1 KO mice were coinjected with CD40 mAb together with anti-TNF-α, anti-IL-12 and IL-23 p40 (anti-p40), or anti-IFN-γ. Anti-p40 had the most marked effect, leading to inhibition of wasting disease, increases in serum cytokines, and colon immune pathology (Figure 3, Figure 4). Anti-TNF-α and anti-IFN-γ also significantly inhibited wasting, although neither afforded complete protection from increases in serum cytokine levels or colitis (Figure 3). Together the data indicate that proinflammatory cytokines play a key role in anti-CD40-induced systemic and intestinal immune pathology.Figure 4CD40-Induced Intestinal Immunopathology Depends Functionally on IL-23p19Show full captionRag1 KO mice were either left untreated or injected with 125 μg of anti-CD40. In some groups, IL-12 and IL-23p40 (anti-p40; 500 μg), IL-23p19 (anti-p19, 1 mg), or isotype control (1 mg) mAbs were coinjected together with anti-CD40 at day 0 and 3 and analyzed for weight, serum cytokine concentration, and development of colitis. Data are representative of three independent experiments. Mean value is shown ± SD, and significance was tested by the Mann and Whitney U test.(A) Weight as a percentage of the initial weight (n = 7 per group); ∗untreated versus isotype control p < 0.001 and isotype control versus anti-p19 p < 0.001.(B) TNF-α, IL-6, and MCP-1 serum concentration at day 3 (n = 7 per group). ND, not determined.(C) H&E staining of proximal colon at day 7. Anti-CD40-mediated pathology including epithelial hyperplasia, lamina propria infiltration, and a reduction of goblet cells was completely inhibited by blocking with anti-p40 or anti-p19. Colitis score (n = 4–7 mice per group).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Rag1 KO mice were either left untreated or injected with 125 μg of anti-CD40. In some groups, IL-12 and IL-23p40 (anti-p40; 500 μg), IL-23p19 (anti-p19, 1 mg), or isotype control (1 mg) mAbs were coinjected together with anti-CD40 at day 0 and 3 and analyzed for weight, serum cytokine concentration, and development of colitis. Data are representative of three independent experiments. Mean value is shown ± SD, and significance was tested by the Mann and Whitney U test. (A) Weight as a percentage of the initial weight (n = 7 per group); ∗untreated versus isotype control p < 0.001 and isotype control versus anti-p19 p < 0.001. (B) TNF-α, IL-6, and MCP-1 serum concentration at day 3 (n = 7 per group). ND, not determined. (C) H&E staining of proximal colon at day 7. Anti-CD40-mediated pathology including epithelial hyperplasia, lamina propria infiltration, and a reduction of goblet cells was completely inhibited by blocking with anti-p40 or anti-p19. Colitis score (n = 4–7 mice per group). Anti-IL-12p40 neutralizes the activity not only of IL-12 (p35p40) but also IL-23, which is composed of a heterodimer of p40 with p19 (Trinchieri et al., 2003Trinchieri G. Pflanz S. Kastelein R.A. The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses.Immunity. 2003; 19: 641-644Abstract Full Text Full Text PDF PubMed Scopus (757) Google Scholar). To unravel the role of IL-23 in this system, immunodeficient mice were coinjected with anti-CD40 together with neutralizing anti-IL-12 and -23p40 (anti-p40), anti-IL-23p19 (anti-p19), or an isotype control antibody. Anti-p40 inhibited systemic immune activation as well as local colonic pathology (Figure 4). In contrast, anti-CD40 and anti-p19 coinjected mice developed wasting disease (Figure 4A) and showed serum amounts of the inflammatory mediators MCP-1, IL-6, and TNF-α that were similar to anti-CD40-treated controls (Figure 4B). Strikingly, anti-IL-23p19-treated mice did not develop signs of intestinal inflammation (Figure 4C). These experiments suggest differential roles for IL-12 and IL-23 in systemic and mucosal innate immunopathology. To further investigate this, we crossed mice that are deficient for IL-12p35 or IL-23p19 as well as IL-12 and IL-23p40 onto a Rag1-deficient background (Rag1 p35 DKO, Rag1 p19 DKO, Rag1 p40 DKO). These double knockout mice were injected with anti-CD40. Rag1 p40 DKO mice were protected from anti-CD40-induced wasting disease and splenomegaly, had reduced serum cytokine concentrations, and were protected from intestinal pathology (Figures 5A–5D). Rag1 p35 DKO did not develop wasting disease after anti-CD40 stimulation, but intestinal inflammation was present (Figures 5A and 5D). In these mice, reduced splenomegaly was detected, and significantly reduced serum TNF-α was found compared to anti-CD40-treated Rag1 KO mice (Figures 5B and 5C). In contrast, anti-CD40-treated Rag1 p19 DKO mice developed wasting disease, splenomegaly, and elevated serum cytokine amounts (Figures 5A–5C). Despite this systemic immune activation, these mice were protected from intestinal pathology (Figure 5D). To test whether the activity of IL-12 and IL-23 involves the modulation of the intestinal cytokine response, we determined proinflammatory cytokine concentrations within the intestine in the anti-CD40-treated mice. Compared to control mice, anti-CD40-treated mice had increased amounts of colonic TNF-α, MCP-1, and IL-6 (Figure 5E). Similar or greater increases were also present in Rag1 p35 DKO mice, which is in line with the presence of colitis in these mice. In contrast and again consistent with disease score, elevations in inflammatory cytokines were abrogated in anti-CD40-treated Rag1 p40 DKO and Rag1 p19 DKO mice (Figure 5E). In summary, our experiments demonstrate that CD40 stimulation initiates a complex innate immune cascade that drives the development of systemic and local gut immune pathology. In this model, we find that the inflammatory cytokines TNF-α and IL-12 are preferentially linked to the systemic innate immune response, whereas the activity of IL-23 is linked primarily to the intestinal inflammatory response with little functional role in systemic immune activation. To determine whether IL-23 and IL-12 are produced in the intestine, we analyzed the expression of IL-23 p19, IL-12 p35, and IL-12 p40 mRNA in colon and spleen at D7 after CD40 mAb injection via real-time reverse-transcription polymerase chain reaction (RT-PCR). Relative to untreated control spleen or colon, there was an increase in both IL-23 p19 and IL-12 p35 subunits in both compartments after anti-CD40 stimulation (Figure 6A). We did not observe an increase in IL-12 p40 subunit, because p40 mRNA was expressed at a high amount prior to injection (data not shown). Consistent with the mRNA expression data, increased concentrations of IL-23 protein were detected in the culture supernatants of colon from anti-CD40-treated mice compared to controls (Figure 6B). Anti-CD40 stimulation led to myeloid cell activation and accumulation, so we next investigated whether these cells are a potential source of IL-23. CD11chi (DC) and CD11b+CD11c− (monocytic) cells were isolated by FACS sorting from spleen and colon 7 days after anti-CD40 stimulation, and IL-23 p19, IL-12 and IL-23 p40, and IL-12 p35 gene expression was determined by real-time RT-PCR. Relative to HPRT, the highest amount of anti-CD40-induced IL-23 p19 mRNA was found among colonic DC (Figure S3). These cells expressed a striking 568-fold increase compared to resting splenic DC and 69-fold higher amount than activated splenic DC (Figure S3). This is likely to reflect functional IL-23, because both splenic and colonic DC populations expressed high amounts of IL-12 and IL-23 p40 (Figure S3). Colonic monocytes may also contribute to local IL-23 production, as indicated by the fact that they too expressed high amounts of IL-23 p19 mRNA (Figure S3). As expected, there was also an increase in IL-12 p35, relative to amounts in resting splenic populations, among DC and monocyte or macrophages isolated from the spleen and colon of anti-CD40-treated mice. The IL-12 p35 increase was largest among colonic monocyte or macrophages (106-fold higher). It is worth noting, however, that for activated colonic DC, the increase in IL-12 p35 (7-fold) was substantially lower than the increase in IL-23 p19 (568-fold). Together, the data suggest that anti-CD40 stimulation induces IL-23 expression by both DC and monocyte or macrophage populations and that for the former this is most pronounced in the colon. Immune pathological responses associated with IL-23 are thought to involve promotion of IL-17-producing T cells (Hunter, 2005Hunter C.A. New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions.Nat. Rev. Immunol. 2005; 5: 521-531Crossref PubMed Scopus (636) Google Scholar, McKenzie et al., 2005McKenzie B.S. Kastelein R.A. Cua D.J. Understanding the IL-23-IL-17 immune pathway.Trends Immunol. 2005; 27: 17-23Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar). To determine whether IL-23-mediated innate inflammation is also linked to increased IL-17 production, we examined the expression of IL-17 mRNA (now termed IL-17A) in colon and spleen of Rag1 KO mice after CD40 mAb injection. As shown in Figure 6C, compared to colons from unstimulated mice, there was a 65-fold increase in IL-17 transcripts after anti-CD40 stimulation. However, no such increase was observed in the spleen. As with other inflammatory cytokines, increases in colonic IL-17 mRNA were dependent on IL-23 and not IL-12 (Figure 6D). These results indicate that anti-CD40 stimulation induces IL-17 mRNA production by non-T cells and that this response is localized to the colon. The IBDs are of complex multifactorial pathogenesis and involve the activation of the innate and adaptive immune system. Animal models have suggested T cell-dependent and -independent mechanisms of intestinal inflammation (Strober et al., 2002Strober W. Fuss I.J. Blumberg R.S. The immunology of mucosal models of inflammation.Annu. Rev. Immunol. 2002; 20: 495-549Crossref PubMed Scopus (1105) Google Scholar). In IBD, there is evidence that alterations in the innate immune response contribute to disease development because mutations in the NOD2 gene, which lead to abnormal function of this innate pathogen recognition receptor, confer susceptibility to CD in some patients (Eckmann and Karin, 2005Eckmann L. Karin M. NOD2 and Crohn's disease: loss or gain of function?.Immunity. 2005; 22: 661-667Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar). In IBD patients as well as in many model situations, the CD40L-CD40 pathway plays an important role in the crosstalk between the innate and adaptive immune response. We therefore developed a model where CD40L-expressing activated T cells were replaced with an agonist CD40 mAb and demonstrate that CD40-mediated effector function, in the absence of further T cell help, is sufficient to induce a pathogenic systemic and local inflammatory response. Anti-CD40-induced disease is accompanied by accumulation of myeloid cells including activated cytokine-producing DC in spleen and colon. Production of the inflammatory cytokine IL-12 and IL-23p40 subunit plays a pivotal role in the pathogenesis of systemic and mucosal disease. To date, the functions of IL-23 have only been described in models that involve T cells (Cua et al., 2003Cua D.J. Sherlock J. Chen Y. Murphy C.A. Joyce B. Seymour B. Lucian L. To W. Kwan S. Churakova T. et al.Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.Nature. 2003; 421: 744-748Crossref PubMed Scopus (2245) Google Scholar, Murphy et al., 2003Murphy C.A. Langrish C.L. Chen Y. Blumenschein W. McClanahan T. Kastelein R.A. Sedgwick J.D. Cua D.J. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation.J. Exp. Med. 2003; 198: 1951-1957Crossref PubMed Scopus (1334) Google Scholar). However, our data reveal distinct roles for IL-12 and IL-23 within the innate immune system. Thus, IL-12 is a key molecule for systemic immune activation whereas IL-23 drives local intestinal inflammation. With our model of innate immune activation, we show that a number of proinflammatory cytokines are associated with weight loss and colon pathology. Inhibition of TNF-α and IFN-γ had some protective effect on the systemic immune pathology and colitis, but only blockade of the p40 subunit of IL-12 and IL-23 completely prevented wasting and colitis. These results suggest that IL-12 and IL-23p40 is a key factor within the proinflammatory cytokine cascade. There is considerable evidence that early expression of IL-12 and/or IL-23 directs a variety of downstream effectors of inflammation (for reviews, see Hunter, 2005Hunter C.A. New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions.Nat. Rev. Immunol. 2005; 5: 521-531Crossref PubMed Scopus (636) Google Scholar, Langrish et al., 2004Langrish C.L. McKenzie B.S. Wilson N.J. de Waal Malefyt R. Kastelein R.A. Cua D.J. IL-12 and IL-23: master regulators of innate and adaptive immunity.Immunol. Rev. 2004; 202: 96-105Crossref PubMed Scopus (575) Google Scholar, Trinchieri et al., 2003Trinchieri G. Pflanz S. Kastelein R.A. The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses.Immunity. 2003; 19: 641-644Abstract Full Text Full Text PDF PubMed Scopus (757) Google Scholar, McKenzie et al., 2005McKenzie B.S. Kastelein R.A. Cua D.J. Understanding the IL-23-IL-17 immune pathway.Trends Immunol. 2005; 27: 17-23Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar). Thus, it is likely that the inflammatory cascade induced by CD40 ligation triggers the production of IL-12 and/or IL-23, which induces the release of other proinflammatory cytokines such as TNF-α, IFN-γ, and IL-6 by DC and macrophages as well as IFN-γ by NK cells (Ma, 2001Ma X. TNF-alpha and IL-12: a balancing act in macrophage functioning.Microbes Infect. 2001; 3: 121-129Crossref PubMed Scopus (96) Google Scholar, Mason et al., 2002Mason N. Aliberti J. Caamano J.C. Liou H.C. Hunter C.A. Cutting edge: identification of c-Rel-dependent and -independent pathways of IL-12 production during infectious and inflammatory stimuli.J. Immunol. 2002; 168: 2590-2594PubMed Google Scholar). Indeed, we found that myeloid cells, in particular CD40-expressing CD80+CD86+MHC-II+CD11c+ DC become activated after anti-CD40 stimulation and that IL-12 and IL-23 mRNA-producing monocytic cells and DCs accumulate within the colon and spleen. The presence of IFN-γ acts synergistically with CD40 stimulation (Cua et al., 2003Cua D.J. Sherlock J. Chen Y. Murphy C.A. Joyce B. Seymour B. Lucian L. To W. Kwan S. Churakova T. et al.Interleukin-23 rather than interleukin-12 is the" @default.
• W2167264906 created "2016-06-24" @default.
• W2167264906 creator A5001196794 @default.
• W2167264906 creator A5003762680 @default.
• W2167264906 creator A5022492796 @default.
• W2167264906 creator A5039199346 @default.
• W2167264906 creator A5047497607 @default.
• W2167264906 creator A5059550425 @default.
• W2167264906 creator A5060811419 @default.
• W2167264906 creator A5061444710 @default.
• W2167264906 creator A5065441188 @default.
• W2167264906 creator A5068596046 @default.
• W2167264906 creator A5072236687 @default.
• W2167264906 date "2006-08-01" @default.
• W2167264906 modified "2023-10-17" @default.
• W2167264906 title "Differential Activity of IL-12 and IL-23 in Mucosal and Systemic Innate Immune Pathology" @default.
• W2167264906 cites W1514253734 @default.
• W2167264906 cites W1514782836 @default.
• W2167264906 cites W1666489731 @default.
• W2167264906 cites W1847326477 @default.
• W2167264906 cites W1929074972 @default.
• W2167264906 cites W1966999437 @default.
• W2167264906 cites W1968918322 @default.
• W2167264906 cites W1971119469 @default.
• W2167264906 cites W1976783221 @default.
• W2167264906 cites W1984251298 @default.
• W2167264906 cites W1987628377 @default.
• W2167264906 cites W2006249161 @default.
• W2167264906 cites W2017443683 @default.
• W2167264906 cites W2031778684 @default.
• W2167264906 cites W2035027025 @default.
• W2167264906 cites W2042322494 @default.
• W2167264906 cites W2043222665 @default.
• W2167264906 cites W2052435488 @default.
• W2167264906 cites W2062160650 @default.
• W2167264906 cites W2062528530 @default.
• W2167264906 cites W2065792169 @default.
• W2167264906 cites W2069968649 @default.
• W2167264906 cites W2076889715 @default.
• W2167264906 cites W2087905758 @default.
• W2167264906 cites W2093531092 @default.
• W2167264906 cites W2094373273 @default.
• W2167264906 cites W2099376515 @default.
• W2167264906 cites W2101492664 @default.
• W2167264906 cites W2107235439 @default.
• W2167264906 cites W2112546054 @default.
• W2167264906 cites W2113257038 @default.
• W2167264906 cites W2113285613 @default.
• W2167264906 cites W2116828514 @default.
• W2167264906 cites W2120312540 @default.
• W2167264906 cites W2128090799 @default.
• W2167264906 cites W2131727319 @default.
• W2167264906 cites W2141679700 @default.
• W2167264906 cites W2149400414 @default.
• W2167264906 cites W2155386017 @default.
• W2167264906 cites W2325682891 @default.
• W2167264906 cites W4238322028 @default.
• W2167264906 doi "https://doi.org/10.1016/j.immuni.2006.05.017" @default.
• W2167264906 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/16919486" @default.
• W2167264906 hasPublicationYear "2006" @default.
• W2167264906 type Work @default.
• W2167264906 sameAs 2167264906 @default.
• W2167264906 citedByCount "618" @default.
• W2167264906 countsByYear W21672649062012 @default.
• W2167264906 countsByYear W21672649062013 @default.
• W2167264906 countsByYear W21672649062014 @default.
• W2167264906 countsByYear W21672649062015 @default.
• W2167264906 countsByYear W21672649062016 @default.
• W2167264906 countsByYear W21672649062017 @default.
• W2167264906 countsByYear W21672649062018 @default.
• W2167264906 countsByYear W21672649062019 @default.
• W2167264906 countsByYear W21672649062020 @default.
• W2167264906 countsByYear W21672649062021 @default.
• W2167264906 countsByYear W21672649062022 @default.
• W2167264906 countsByYear W21672649062023 @default.
• W2167264906 crossrefType "journal-article" @default.
• W2167264906 hasAuthorship W2167264906A5001196794 @default.
• W2167264906 hasAuthorship W2167264906A5003762680 @default.
• W2167264906 hasAuthorship W2167264906A5022492796 @default.
• W2167264906 hasAuthorship W2167264906A5039199346 @default.
• W2167264906 hasAuthorship W2167264906A5047497607 @default.
• W2167264906 hasAuthorship W2167264906A5059550425 @default.
• W2167264906 hasAuthorship W2167264906A5060811419 @default.
• W2167264906 hasAuthorship W2167264906A5061444710 @default.
• W2167264906 hasAuthorship W2167264906A5065441188 @default.
• W2167264906 hasAuthorship W2167264906A5068596046 @default.
• W2167264906 hasAuthorship W2167264906A5072236687 @default.
• W2167264906 hasBestOaLocation W21672649061 @default.
• W2167264906 hasConcept C136449434 @default.
• W2167264906 hasConcept C203014093 @default.
• W2167264906 hasConcept C47742525 @default.
• W2167264906 hasConcept C86803240 @default.
• W2167264906 hasConcept C8891405 @default.
• W2167264906 hasConceptScore W2167264906C136449434 @default.
• W2167264906 hasConceptScore W2167264906C203014093 @default.
• W2167264906 hasConceptScore W2167264906C47742525 @default.
• W2167264906 hasConceptScore W2167264906C86803240 @default.
• W2167264906 hasConceptScore W2167264906C8891405 @default.

• next