Martin C A, Dorf M E
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115.
Cell Immunol. 1991 Jun;135(1):245-58. doi: 10.1016/0008-8749(91)90269-h.
Activated macrophages produce a number of proinflammatory cytokines including IL-6, JE, MIP-1 alpha and MIP-1 beta. The induction requirements for production of either IL-6 or the MIP-1 related inflammatory proteins (MIP-1 alpha, MIP-1 beta, and JE) have been analyzed independently using fibroblasts, monocytes, or endothelial cells. However, little is known about the regulation of these cytokines in macrophages. Since activated macrophages produce prostaglandins (PGE2) which may participate in the autoregulation of cytokine production by stimulation of adenylate cyclase and the induction of cAMP-dependent signal pathways, we determined the effects of PGE on the production of IL-6 and MIP-1-related proteins. Murine macrophage cell lines were incubated with PGE1, PGE2, cholera toxin, or dibutyryl cAMP in the presence of absence suboptimal doses of LPS. Pharmacologic agents alone did not induce IL-6 production but incubation of macrophages with combinations of adenylate cyclase stimulators and LPS or dcAMP and LPS led to the dose-dependent enhancement of IL-6 secretion and mRNA expression. In contrast, PGE1 inhibits LPS-induced JE, MIP-1 alpha, and MIP-1 beta mRNA expression and this inhibition is partially dependent on a cAMP-mediated pathway of signal transduction. In previous work we demonstrated that IFN-gamma and PMA do not stimulate the production of IL-6 by macrophages. Here we show that incubation of macrophages with either IFN-gamma or PMA induces the expression of JE, MIP-1 alpha and MIP-1 beta mRNA expression. JE mRNA expression is much more responsive to the stimulatory effects of IFN-gamma than are the MIP-1 genes. Finally, PGE inhibits PMA and IFN-gamma-induced JE and MIP-1-related mRNA expression.
活化的巨噬细胞会产生多种促炎细胞因子，包括白细胞介素-6（IL-6）、JE、巨噬细胞炎性蛋白-1α（MIP-1α）和巨噬细胞炎性蛋白-1β（MIP-1β）。对于IL-6或与MIP-1相关的炎性蛋白（MIP-1α、MIP-1β和JE）的产生诱导需求，已分别使用成纤维细胞、单核细胞或内皮细胞进行了分析。然而，对于巨噬细胞中这些细胞因子的调节知之甚少。由于活化的巨噬细胞会产生前列腺素（PGE2），其可能通过刺激腺苷酸环化酶和诱导cAMP依赖性信号通路参与细胞因子产生的自动调节，因此我们确定了PGE对IL-6和MIP-1相关蛋白产生的影响。在存在或不存在次优剂量脂多糖（LPS）的情况下，将小鼠巨噬细胞系与PGE1、PGE2、霍乱毒素或二丁酰cAMP一起孵育。单独的药理剂不会诱导IL-6的产生，但巨噬细胞与腺苷酸环化酶刺激剂和LPS或二丁酰cAMP和LPS的组合孵育会导致IL-6分泌和mRNA表达呈剂量依赖性增强。相反，PGE1会抑制LPS诱导的JE、MIP-1α和MIP-1β mRNA表达，且这种抑制部分依赖于cAMP介导的信号转导途径。在之前的工作中，我们证明干扰素-γ（IFN-γ）和佛波酯（PMA）不会刺激巨噬细胞产生IL-6。在此我们表明，巨噬细胞与IFN-γ或PMA一起孵育会诱导JE、MIP-1α和MIP-1β mRNA表达。JE mRNA表达对IFN-γ刺激作用的反应比MIP-1基因更敏感。最后，PGE会抑制PMA和IFN-γ诱导的JE和MIP-1相关mRNA表达。
