[Mechanism of production and release of tumor necrosis factor implicated in inflammatory diseases].
Tumor necrosis factor (TNF) is a potent inflammatory cytokine involved in many pathophysiological conditions including rheumatoid arthritis and Crohn's disease. Despite recent evidence regarding signal transduction via TNF receptor and its biological actions, the mechanism of TNF release remains poorly understood. To clarify how production and release of TNF are regulated, we focused on mast cells and microglia which are involved in allergic inflammation and brain damage or recovery, respectively. In RBL-2H3 mast cells, anti-allergic drugs including azelastine inhibited the release of TNF more potently than degranulation in response to antigen or ionomycin. It was also demonstrated that TNF releasing steps are regulated via the PKC alpha-dependent pathway. Furthermore, Rho GTPases, possibly Rac, were shown to be involved in antigen-induced TNF transcription through activating PKC beta I. In cultured rat brain microglia, we found that extracellular ATP triggers the release of TNF via the P2X7 receptor. ERK and JNK are also involved in ATP-induced TNF transcription, while p38 regulates the transport of TNF mRNA from the nucleus to the cytosol. Additionally, JNK and p38, but not ERK, are activated via the P2X7 receptor. A better understanding of the specific pathways that regulate TNF release for each effector cell may offer further possible therapeutic targets for inflammatory diseases.
Hide
Izumi
I
Department of Pharmacology, Graduate School of Biomedical Sciences, Hiroshima University, Kasumi, Minami-ku, Hiroshima 743-8551, Japan. ihide@hiroshima-u.ac.jp
D000255:Adenosine Triphosphate / Q000502:physiology; D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D006967:Hypersensitivity / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism*; D018836:Inflammation Mediators; D008407:Mast Cells / Q000378:metabolism; D017628:Microglia / Q000378:metabolism; D010793:Phthalazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000502:physiology; D058486:Receptors, Purinergic P2X7; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000502:physiology; D020741:rho GTP-Binding Proteins / Q000502:physiology
D018926:Anti-Allergic Agents; D018836:Inflammation Mediators; C546468:P2RX7 protein, human; C546470:P2rx7 protein, rat; D010793:Phthalazines; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate; D011493:Protein Kinase C; D020741:rho GTP-Binding Proteins; C020976:azelastine