Stewart A G, Harris T, De Nichilo M, Lopez A F
Department of Physiology, University of Melbourne, Parkville, Victoria, Australia.
Immunology. 1991 Feb;72(2):206-12.
Recombinant human (rh) tumour necrosis factor (TNF) alpha and rh granulocyte-macrophage colony-stimulating factor (GM-CSF) prime human polymorphonuclear leucocytes (PMN) for increased superoxide anion (O2-) generation and for increased platelet-activating factor (PAF) biosynthesis and leukotriene B4 (LTB4) release. Both PAF and LTB4 are candidate mediators for the enhanced O2- generation in cytokine-primed PMN, since exogenous PAF or LTB4 primes PMN. We measured the generation and release of these mediators and examined their potential roles in cytokine priming using the PAF receptor antagonist, WEB 2086, and the inhibitor of 5-lipo-oxygenase, CGS 8515.rhTNF-alpha or rhGM-CSF, alone, increased PAF levels in PMN, but did not cause PAF release or LTB4 synthesis. N-formylmethionyl-leucyl-phenylalanine (FMLP) stimulated the release of detectable and biologically active amounts of both LTB4 and PAF in primed, but not in non-primed PMN. However, neither blockade of PAF receptors, nor inhibition of LTB4 synthesis influenced the priming of O2- generation by rhTNF-alpha or rhGM-CSF. Simultaneous pretreatment of PMN with WEB 2086 and CGS 8515 also failed to inhibit priming. Our results do not exclude a role for cell-associated PAF in the priming response, but indicate that the release of PAF and LTB4 do not mediate this phenomenon. The ability of cytokines to amplify the production and release of lipids may represent a mechanism to attract and localize the pro-inflammatory actions of stimulated PMN to regions where cytokine levels are also elevated.
重组人（rh）肿瘤坏死因子（TNF）α和rh粒细胞-巨噬细胞集落刺激因子（GM-CSF）可使人类多形核白细胞（PMN）致敏，从而增加超氧阴离子（O2-）的生成，以及增加血小板活化因子（PAF）的生物合成和白三烯B4（LTB4）的释放。PAF和LTB4都是细胞因子致敏的PMN中O2-生成增强的潜在介质，因为外源性PAF或LTB4可使PMN致敏。我们测量了这些介质的生成和释放，并使用PAF受体拮抗剂WEB 2086和5-脂氧合酶抑制剂CGS 8515研究了它们在细胞因子致敏中的潜在作用。单独的rhTNF-α或rhGM-CSF可增加PMN中的PAF水平，但不会导致PAF释放或LTB4合成。N-甲酰甲硫氨酰-亮氨酰-苯丙氨酸（FMLP）刺激致敏但未致敏的PMN释放可检测到的且具有生物活性的LTB4和PAF。然而，阻断PAF受体或抑制LTB4合成均不影响rhTNF-α或rhGM-CSF对O2-生成的致敏作用。用WEB 2086和CGS 8515同时预处理PMN也未能抑制致敏作用。我们的结果不排除细胞相关PAF在致敏反应中的作用，但表明PAF和LTB4的释放并不介导这一现象。细胞因子放大脂质产生和释放的能力可能代表一种机制，可将受刺激的PMN的促炎作用吸引并定位到细胞因子水平也升高的区域。
