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Tumor Necrosis Factor-α Develops Late Anaphylactic Reaction through Cytosolic Phospholipase A2 ActivationKang N.-I.a · Kim H.-K.a, b · Ko H.-M.c · Kim J.-H.d · You H.-J.d · Choi I.-W.e · Im S.-Y.c · Lee H.-K.a
aDepartment of Immunology, Chonbuk National University Medical School, Jeonju, bRadiation Research Center for Industry and Environment, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, cDepartment of Biological Sciences, College of Natural Sciences, Chonnam National University, Gwangju, dKorea University School of Life Sciences and Biotechnology, Seoul, and eDepartment of Microbiology, Inje University College of Medicine, Busan, Republic of Korea
Background: We have recently reported that tumor necrosis factor (TNF)-α plays an important role in the development of a late anaphylactic reaction, but the downstream pathway beyond TNF-α remains unclear. Objective: It was the aim of this study to examine whether TNF-α induces late-phase anaphylaxis via the activation of cytosolic phospholipase A2 (cPLA2). Methods: Using a murine model of active systemic anaphylaxis to penicillin V, the induction of the late phase of anaphylaxis was quantified by measuring the increase in hematocrit value as well as the plasma level of platelet-activating factor in TNF-α knockout mice. Phosphorylation of mitogen-activated protein kinases (MAPKs) and cPLA2 was measured by immunoprecipitation. cPLA2 activity was assessed by using 1-stearoyl-2-[1-14C] arachidonyl-sn-glycero-3-phosphocholine as the substrate. Results: Phosphorylation and enzymatic activity of cPLA2, and phosphorylation of the 3 known MAPKs, i.e. p38, extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun NH2-terminal kinase, were markedly increased in a TNF-α-dependent way in the lungs of mice undergoing anaphylaxis. A specific cPLA2 inhibitor significantly attenuated the late anaphylactic symptoms. Either p38 or an ERK inhibitor significantly attenuated not only cPLA2 phosphorylation and activity, but also the late-phase anaphylaxis. Conclusion: TNF-α-induces cPLA2 activation through the pathway involving p38 MAPK and ERK activation and appears to be the key mechanism leading to the development of late-phase anaphylaxis.
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