The Interleukin-1β-Converting Enzyme Inhibitor Pralnacasan Reduces Dextran Sulfate Sodium-Induced Murine Colitis and T Helper 1 T-Cell Activation

Loher, Florian; Bauer, Christian; Landauer, Nikola; Schmall, Kathrin; Siegmund, Britta; Lehr, Hans A.; Dauer, Marc; Schoenharting, Martin; Endres, Stefan; Eigler, Andreas

doi:10.1124/jpet.103.057059

Cited by 107 publications

(76 citation statements)

References 27 publications

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“…Consistent with this, we found that infiltration of neutrophils and macrophages into the CNS during the development of EAE, which is driven by Th17 and Th1 cells, respectively, was attenuated by treatment with the caspase-1 inhibitor. Caspase-1 inhibitors have already shown efficacy in experimental models of multiple sclerosis, colitis, pancreatitis, and seizure (29,(31)(32)(33)(34). Pralnacasan, a caspase-1 inhibitor, has also shown some efficacy in phase II clinic trails in rheumatoid arthritis patients, but the trial was discontinued because of toxicity issues in long-term animal studies (35).…”

Section: Discussionmentioning

confidence: 99%

Caspase-1–Processed Cytokines IL-1β and IL-18 Promote IL-17 Production by γδ and CD4 T Cells That Mediate Autoimmunity

Lalor

Dungan

Sutton

et al. 2011

The Journal of Immunology

323

260

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IL-1β plays a critical role in promoting IL-17 production by γδ and CD4 T cells. However, IL-1–targeted drugs, although effective against autoinflammatory diseases, are less effective against autoimmune diseases. Conversely, gain-of-function mutations in the NLRP3 inflammasome complex are associated with enhanced IL-1β and IL-18 production and Th17 responses. In this study, we examined the role of caspase-1–processed cytokines in IL-17 production and in induction of experimental autoimmune encephalomyelitis (EAE). Killed Mycobacterium tuberculosis, the immunostimulatory component in CFA used for inducing EAE, stimulated IL-1β and IL-18 production by dendritic cells through activation of the inflammasome complex and caspase-1. Dendritic cells stimulated with M. tuberculosis and myelin oligodendrocyte glycoprotein promoted IL-17 production by T cells and induced EAE following transfer to naive mice, and this was suppressed by a caspase-1 inhibitor and reversed by administration of IL-1β or IL-18. Direct injection of the caspase-1 inhibitor suppressed IL-17 production by CD4 T cells and γδ T cells in vivo and attenuated the clinical signs of EAE. γδ T cells expressed high levels of IL-18R and the combination of IL-18 and IL-23, as with IL-1β and IL-23, stimulated IL-17 production by γδ T cells, but also from CD4 T cells, in the absence of TCR engagement. Our findings demonstrate that caspase-1–processed cytokines IL-1β and IL-18 not only promote autoimmunity by stimulating innate IL-17 production by T cells but also reveal redundancy in the functions of IL-1β and IL-18, suggesting that caspase-1 or the inflammasome may be an important drug target for autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

Caspase-1–Processed Cytokines IL-1β and IL-18 Promote IL-17 Production by γδ and CD4 T Cells That Mediate Autoimmunity

Lalor

Dungan

Sutton

et al. 2011

The Journal of Immunology

323

260

View full text Add to dashboard Cite

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“…Tissue levels of IL-8 have been reported to be upregulated in cases of CD and UC (37). IL-1␤ is crucial to IBD pathology, and its inhibition has been shown to attenuate DSS colitis through inhibition of proinflammatory activity and possibly downstream proangiogenic activity (91). IL-12 and IL-18 are inducers of IFN-␥ and TNF-␣ production in lymphocytes; however, observations in DSS colitis revealed that IL-12 Ϫ/Ϫ mice develop mild colitis whereas IL-18 Ϫ/Ϫ mice develop severe colitis, indicating that IL-12 may be more protective than IL-18 (152).…”

Section: Angiogenic Mediators In Ibd and Experimental Colitismentioning

confidence: 99%

Pathogenic angiogenesis in IBD and experimental colitis: new ideas and therapeutic avenues

Chidlow

Shukla²,

Grisham³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

145

114

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Chidlow JH Jr, Shukla D, Grisham MB, Kevil CG. Pathogenic angiogenesis in IBD and experimental colitis: new ideas and therapeutic avenues. Am J Physiol Gastrointest Liver Physiol 293: G5-G18, 2007. First published April 26, 2007; doi:10.1152/ajpgi.00107.2007.-Angiogenesis is now understood to play a major role in the pathology of chronic inflammatory diseases and is indicated to exacerbate disease pathology. Recent evidence shows that angiogenesis is crucial during inflammatory bowel disease (IBD) and in experimental models of colitis. Examination of the relationship between angiogenesis and inflammation in experimental colitis shows that initiating factors for these responses simultaneously increase as disease progresses and correlate in magnitude. Recent studies show that inhibition of the inflammatory response attenuates angiogenesis to a similar degree and, importantly, that inhibition of angiogenesis does the same to inflammation. Recent data provide evidence that differential regulation of the angiogenic mediators involved in IBD-associated chronic inflammation is the root of this pathological angiogenesis. Many factors are involved in this phenomenon, including growth factors/cytokines, chemokines, adhesion molecules, integrins, matrix-associated molecules, and signaling targets. These factors are produced by various vascular, inflammatory, and immune cell types that are involved in IBD pathology. Moreover, recent studies provide evidence that antiangiogenic therapy is a novel and effective approach for IBD treatment. Here we review the role of pathological angiogenesis during IBD and experimental colitis and discuss the therapeutic avenues this recent knowledge has revealed. inflammation; T cells; growth factors; adhesion molecules; antiangiogenesis ANGIOGENESIS PLAYS AN IMPORTANT role in many chronic inflammatory diseases including but not limited to diabetic retinopathy, atherosclerosis, rheumatoid arthritis, hypercholesterolemia, and psoriasis. It has been suggested that the angiogenic components of these diseases contribute to and exacerbate disease conditions (26, 31). Recent findings, both clinical and experimental, indicate that angiogenesis also plays a crucial role in the inflammatory bowel diseases (IBD), consisting of Crohn's disease (CD) and ulcerative colitis (UC) (31,37,58,131,155). Development of new vasculature during chronic inflammation may play a negative "pathological" role by contributing to increased inflammatory responses due to dysfunctional new vessel architecture and increases in the recruitment of inflammatory cell types. Importantly, recent data have shown that angiogenic inhibition during chronic inflammatory diseases attenuates further inflammation and disease pathology (31, 37, 51). As such, expanding our knowledge of how pathological angiogenesis occurs during IBD will further our ability to treat patients with these diseases. IBD PathogenesisCD and UC are idiopathic inflammatory disorders of the intestine and/or colon in which patients suffer from rectal bleeding, severe...

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“…Disorder of autoimmunity is closely related to the imbalance of Th 1 and Th 2 cells. For IFN-γ being on Th 1 cell, abnormal expressions of IFN-γ and IFN-γ mRNA cause inevitably the imbalance of Th 1 /Th 2 and result in immune disorder [38][39][40] . CD 11a + /CD 18 + are cell surface adhesive albumin, also known as lymphocyte function antigen-l (LFA-l), a representative of β 2 integrants.…”

Section: Discussionmentioning

confidence: 99%

Effect of traditional Chinese medicinal enemas on ulcerative colitis of rats

Guo

Tong²,

Bai³

et al. 2004

WJG

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AIM:To investigate the effects of traditional Chinese medicinal enema (TCME) on inflammatory and immune response of colonic mucosa of rats with ulcerative colitis (UC), and to observe the pathogenic mechanism. METHODS:Thirty UC rats, induced by intestinal enema together with 2.4-dinitrochlorobenzene (DNCB) and acetic acid, were randomly divided into 3 groups, i.e., GI, GII and GIII. Groups GI and GII were administered with TCME and salazosulfapyridine enema (SASPE), respectively. Group GIII was clystered with only normal saline (NSE), served as control. Group GIV was taken from normal rats as reference, once daily, from the 7th day after the establishment of UC for total 28 d. Interleukin-6 (IL-6) in the colonic mucosa was assayed by (16.28±0.19%) were raised. There was no significant difference between groups GI and GIV, but the difference between groups GI and GII was quite obvious (P<0.05). The expressions of TNF-α mRNA and IFN-γ mRNA in group GIII were much higher than those of group GIV, but those in group GI were significantly suppressed by TCME therapy. CONCLUSION:Ulcerative colitis is related to colonic regional mucosal inflammatory factors and immune imbalance. TCME can effectively inhibit regional mucosal inflammatory factors and improve their disorder of immunity.Guo SM, Tong HB, Bai LS, Yang W. Effect of traditional Chinese medicinal enemas on ulcerative colitis of rats.

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The Interleukin-1β-Converting Enzyme Inhibitor Pralnacasan Reduces Dextran Sulfate Sodium-Induced Murine Colitis and T Helper 1 T-Cell Activation

Cited by 107 publications

References 27 publications

Caspase-1–Processed Cytokines IL-1β and IL-18 Promote IL-17 Production by γδ and CD4 T Cells That Mediate Autoimmunity

Caspase-1–Processed Cytokines IL-1β and IL-18 Promote IL-17 Production by γδ and CD4 T Cells That Mediate Autoimmunity

Pathogenic angiogenesis in IBD and experimental colitis: new ideas and therapeutic avenues

Effect of traditional Chinese medicinal enemas on ulcerative colitis of rats

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