Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin (IL)-18 is a member of the IL-1 cytokine family. Pro-IL-18 is cleaved by caspase-1 (IL-1beta-converting enzyme) to yield biologically active 18-kDa IL-18. Interleukin-18 is recognized by a heterodimeric receptor, consisting of a ligand-binding alpha-chain (IL-18Ralpha/IL-1Rrp) and an associating beta-chain (IL-18Rbeta/AcPL), which transmits signals through MyD88/IRAK/TRAF-6 molecules. Interleukin-18 is expressed in various types of cells, including macrophages, keratinocytes, intestinal epitherial cells, osteoblastic cells, chondrocytes, and adrenal cortex cells. Interleukin-18 promotes IFN-gamma production and Th1 helper T-cell development, synergistically with IL-12. However, IL-18 itself shows capabilities to induce IL-4, IL-5, IL-10, and IL-13 from T and natural killer cells. It also induces PGE2 production from activated macrophages. Moreover, many diseases are characterized by the production of IL-18 in the lesion. Taking these data together, our working hypothesis on how IL-18 is involved in "destructive" and "compensatory" pathways is proposed in this issue.
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PMID:Roles of interleukin-18 in tissue destruction and compensatory reactions. 1204 45

Murine models have shown that IL-18 has antiangiogenic and antitumor effects, but little is known about IL-18 production in human tumors. We investigated IL-18 expression in clinically localized prostate cancers by immunohistochemistry and showed that 75% of the prostate cancers studied (27/36 cases) presented with tumor cells producing IL-18. Prostate tumor cell lines PC-3, DU 145 and LNCaP synthesized the immature form of IL-18 (p24). IFN-gamma produced in prostate cancers induced caspase-1 mRNA and IL-18 secretion of tumor cell lines, which was inhibited by the cell-permeable Tyr-Val-Ala-Asp-aldehyde caspase-1 inhibitor (YVAD-CHO). Interestingly, IFN-alpha also induced IL-18 secretion of the poorly differentiated cell line PC-3. PC-3 and DU 145, but not the well-differentiated cell line LNCaP, expressed IL-18R alpha (IL-1Rrp) protein and transcripts for IL-18R beta (AcPL). Exogenous IL-18 increased mitochondrial activity of both cell lines evaluated by the tetrazolium (MTT) assay but did not influence their proliferation. This indicated that prostate tumor cells could secrete IL-18 in response to IFN-gamma in the tumor microenvironment and that IL-18 could act as a autocrine/paracrine factor for the tumor. In the cohort of patients studied, IL-18 expression in prostate cancers (with up to 10% of tumor cells stained) was associated with a favorable outcome and equally predictive as pathologic stage on multivariate analysis (log rank test, p = 0.02). Tumor IL-18 production is a novel physiopathologic feature of prostate cancer and appears to be a favorable event in the course of the disease. Modulation of IL-18 production by interferons could have a beneficial clinical effect, which deserves further investigation.
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PMID:IL-18 is produced by prostate cancer cells and secreted in response to interferons. 1291 59