Effect Of Cytokines In Host Defense And Inflammation

我们之前已经证明，IL-8在正常人的皮肤水泡中积累，并且渗出性中性粒细胞可能在体内炎症部位募集额外的中性粒细胞方面发挥重要的自分泌作用。与人外周血相比，渗出性中性粒细胞大大增加了中性粒细胞趋化剂IL-8的储存，但渗出过程中中性粒细胞IL-8增加的机制尚不明确。去年我们表明，用趋化肽fMet-Leu-Phe （fMLF）或白三烯B4 （LTB4）单独或纤维蛋白原单独治疗外周血中性粒细胞，导致外周血中性粒细胞产生IL-8的增加很少。然而，在纤维蛋白原存在生理浓度的情况下，fMLF或LTB4的化学活性剂量会导致IL-8和蛋白质合成的协同（200倍）诱导。获得的IL-8水平与在渗出细胞中观察到的水平相当。今年，我们发现用纤维蛋白原和化学引诱剂C5a处理的外周血人单核细胞导致IL-8增加150倍。这种增加是通过toll样受体4途径介导的，在该途径突变的患者中，反应大大降低，并且通过抗CD14 （toll样受体4相关的LPS受体）的抗体（MY-4）抑制反应。

We have shown previously IL-8 accumulation into skin blisters of normal humans and that exudative neutrophils may play an important autocrine role in the recruitment of additional neutrophils to inflammatory sites in vivo. Compared with human peripheral blood cells, exudative neutrophils have greatly increased stores of the neutrophil chemoattractant IL-8 but the mechanism for the increase in neutrophil IL-8 during exudation is not defined. Last year we showed that treatment of peripheral blood neutrophils with either the chemotactic peptide fMet-Leu-Phe (fMLF) or leukotriene B4 (LTB4) alone, or fibrinogen alone, results in little increase in the production of IL-8 by peripheral blood neutrophils. However, a chemotactically active dose of fMLF or LTB4 in the presence of a physiological concentration of fibrinogen results in synergistic (200 fold) induction of IL-8 and protein synthesis. The levels of IL-8 obtained are comparable to those observed in exudative cells. This year we showed that peripheral blood human monocytes treated with fibrinogen and the chemoattractant C5a results in a 150 fold increase in IL-8. The increase is mediated through the toll-like receptor 4 pathway as evidenced by greatly reduced response in patients with mutations in this pathway and by inhibition of the response with an antibody (MY-4) against CD14, a toll-like receptor 4-associated LPS receptor.