0000000000490240
AUTHOR
Charles A. Dinarello
Interleukin 1α: a comprehensive review on the role of IL-1α in the pathogenesis and treatment of autoimmune and inflammatory diseases.
Abstract The interleukin (IL)-1 family member IL-1α is a ubiquitous and pivotal pro-inflammatory cytokine. The IL-1α precursor is constitutively present in nearly all cell types in health, but is released upon necrotic cell death as a bioactive mediator. IL-1α is also expressed by infiltrating myeloid cells within injured tissues. The cytokine binds the IL-1 receptor 1 (IL-1R1), as does IL-1β, and induces the same pro-inflammatory effects. Being a bioactive precursor released upon tissue damage and necrotic cell death, IL-1α is central to the pathogenesis of numerous conditions characterized by organ or tissue inflammation. These include conditions affecting the lung and respiratory tract, …
IL-1β-converting enzyme (caspase-1) in intestinal inflammation
IL-1β-converting enzyme (ICE; caspase-1) is the intracellular protease that cleaves the precursors of IL-1β and IL-18 into active cytokines. In the present study, the effect of ICE deficiency was evaluated during experimental colitis in mice. In acute dextran sulfate sodium-induced colitis, ICE-deficient (ICE KO) mice exhibited a greater than 50% decrease of the clinical scores weight loss, diarrhea, rectal bleeding, and colon length, whereas daily treatment with IL-1 receptor antagonist revealed a modest reduction in colitis severity. To further characterize the function of ICE and its role in intestinal inflammation, chronic colitis was induced over a 30-day time period. During this chron…
Neutralization of interleukin-18 reduces severity in murine colitis and intestinal IFN-gamma and TNF-alpha production.
Interleukin (IL)-18, initially described as interferon (IFN)-gamma-inducing factor, is expressed in the inflamed mucosa of patients with Crohn's disease. To investigate the role of IL-18 in intestinal inflammation, the effect of neutralizing antimurine IL-18 antiserum in dextran sulfate sodium (DSS)-induced colitis in BALB/c and C57BL/6 mice was examined. During a dose response of DSS, levels of colonic IL-18 increased parallel with clinical worsening. With the use of confocal laser microscopy, the increased IL-18 was localized to the intestinal epithelial layer. Anti-IL-18 treatment resulted in a dose-dependent reduction of the severity of colitis in both BALB/c and C57BL/6 mice. Colon sho…
Frontline: Interferon regulatory factor-1 as a protective gene in intestinal inflammation: role of TCRγ δ T cells and interleukin-18-binding protein
The transcription factor IFN regulatory factor-1 (IRF-1) regulates production and activity of many inflammatory mediators and cells. Here, we investigated the role of IRF-1 in intestinal inflammation using clinical and histologic scores; inflammatory mediators were also measured in colonic tissue. Dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS) was administered to wild-type (WT) or IRF-1 knockout (KO) mice. DSS or TNBS led to a dramatic increase in lethality and colitis severity in IRF-1 KO compared with WT mice. Reduced levels of IFN-γ and IL-18-binding protein (IL-18BP) were observed in the colon of IRF-1 KO mice, whereas levels of inducible nitric oxide synthase, cyc…