The IL-1 receptor signaling pathway.
Interleukin-1 (IL-1) exerts pleiotropic effects on a variety of tissues through binding to its receptor. Two distinct types of receptors for IL-1 have been characterized in mouse and human. Most of the IL-1 signal has been shown to be transmitted through type I IL-1R (80 kDa) in T lymphocytes as well as B lymphocytes and monocytes. Type II receptor may act as a suppressor of IL-1 biological activities by competing in binding with type I receptors on the cell surface. Functional studies of the type I IL-1R demonstrated that the cytoplasmic segments, possessing a sequence similarity with the Drosophila Toll gene product or IL-6R beta chain, gp130, are important for transmitting activity that induces cytokine genes. In the past three years, several groups reported that IL-1 and tumor necrosis factor (TNF) rapidly induce sphingomyelin turnover in various types of cells, producing ceramide, which may act as a second messenger molecule in an intracellular signaling cascade. Activation of both acid and neutral sphingomyelinases (SMases) has been suggested, and Schutz et al. proposed that the phosphatidylcholine-phospholipase C/acid SMase pathway is involved in TNF-induced NF-kappa B activation. However, our recent study showed that the NF-kappa B activation is induced by IL-1/TNF in fibroblasts from patients with type A Niemann-Pick disease, with acid SMase deficiency. This finding implies that acid SMase activity is not essential for the activation of NF-kappa B by IL-1/TNF at least in fibroblasts. Other signaling pathways including neutral SMase and unidentified protein kinases may be important for NF-kappa B-mediated cytokine gene activation.
Kuno
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Department of Pharmacology, Kanazawa University, Japan.
Matsushima
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D000595:Amino Acid Sequence; D002460:Cell Line; D002518:Ceramides / Q000378:metabolism; D017124:Conserved Sequence; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D007375:Interleukin-1 / Q000378:metabolism*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D017472:Receptors, Interleukin-1 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism; D013329:Structure-Activity Relationship
D002518:Ceramides; D007375:Interleukin-1; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D017472:Receptors, Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D013109:Sphingomyelins; D054746:Cyclic AMP-Dependent Protein Kinase Type II; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D013108:Sphingomyelin Phosphodiesterase