Pathophysiological and pharmacological studies on chemokines

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This study was performed to develop novel types of anti-inflammatory and immunoregulatory agents through elucidating the pathophysiological roles of chemokines including interleukin-8 (IL-8) and monocyte chemotactic and activating factor (MCAF/MCP-1). Through these studies, we obtained the results as follows.#1.In collaboration with Dr.Thestrup-Pedersen's group, we observed that IL-8 recetor expression on B cells was up-regulated in HIV-infected asymptomatic patients, compared with normal persons. Moreover, we observed that B cells from HIV-infeced patients responded differentially to various Th1 and Th2 cytokines, in terms of IL-8 receptor expression.#2.In collaboration with Dr.Thestrup-Pedersen's group, we demonstrated that plasma IL-8 levels elevated immediately after the liver transplantation, probably reflecting reperfusion injury to transplanted organs.#3.In collaboration with Dr.Oppenheim'sgroup, we demonstrated that IL-8 induced the phosphorylation of CXCR2 (IL-8 receptor type B) more strongly, than NAP-2. Moreover, we revealed the strong phosphorylation resulted in reduced neutrophil chemotactic activity in response to high concentrations of IL-8.#4.In collaboration with Dr.Oppenheim, we established a sensitive enzyme-linked immunosorbent assay for a CC hemokine, eotaxin.#5.We established the essential involvement of IL-8 in neutrophil-mediated tissue injuries, such as acute respiratory distress syndrome and brain reperfusion injury model of rabbit. Moreover, we revealed that MCAF/MCP-1 was crucially involved in anti-glomerular basement membrane antisera-induced crescentic shronic glomerulonephritis model.#6.We demonstrated that cytomegalovirus induced IL-8 production in vitro and that IL-8 attenuated anti-viral activities of interferon.The discussion with Drs.Thestrup-Pedersen and Oppenheim has given us invaluable advice when performing studies #5 and #6.