Herriott M J, Jiang H, Stewart C A, Fast D J, Leu R W
Oklahoma Medical Research Foundation, Noble Center for Biomedical Research, Oklahoma City 73104.
J Immunol. 1993 May 15;150(10):4524-31.
Previously we found that murine macrophage migration inhibition (MMI) was mediated by IFN-gamma-priming and lipid A triggering. With the recent availability of human recombinant migration inhibitory factor (MIF), which is distinctly different from IFN-gamma and other cytokines, we have now attempted to explore possible mechanistic differences between IFN-gamma and MIF to mediate MMI. Neither MIF not IFN-gamma were active alone, but effectively primed murine inflammatory macrophages for subsequent triggering by lipid A to mediate MMI. A specific neutralizing antibody for rMIF abrogated MMI mediated only by MIF and not by IFN-gamma-primed macrophages. Distinct differences were also found between the mechanisms by which MIF and IFN-gamma synergized with lipid A for activation in that IFN-gamma-primed and lipid A triggered macrophages produced TNF and nitric oxide (NO), whereas MIF-primed cells did not. Macrophages primed with IFN-gamma and triggered by rTNF were inhibited in their migration, whereas MIF failed to synergize with rTNF for MMI. An inhibitor of NO production NG-monomethyl-L-arginine inhibited MMI mediated by higher activating concentrations of lipid A and by IFN-gamma-primed and lipid A triggered macrophages, but had no effect on MIF-primed cells in concert with lipid A for increased expression of both TNF-alpha mRNA and NO synthase mRNA. Taken together, our results indicate that both MIF and IFN-gamma prime macrophages to synergize with lipid A to mediate MMI but by different mechanisms. The activation process by IFN-gamma to mediate migration inhibition appears to resemble requirements for rendering macrophages tumor cytotoxic in the production of TNF for autocrine-mediated NO generation by primed macrophages. In contrast, MIF-mediated MMI was independent of requirements for either TNF or NO production.
先前我们发现，小鼠巨噬细胞迁移抑制（MMI）是由γ干扰素预处理和脂多糖触发介导的。随着人重组迁移抑制因子（MIF）的问世，它与γ干扰素及其他细胞因子明显不同，我们现在试图探究γ干扰素和MIF在介导MMI方面可能存在的机制差异。MIF和γ干扰素单独作用时均无活性，但均可有效预处理小鼠炎性巨噬细胞，使其随后被脂多糖触发以介导MMI。针对重组人MIF的特异性中和抗体可消除仅由MIF介导的MMI，而不能消除由γ干扰素预处理的巨噬细胞介导的MMI。在MIF和γ干扰素与脂多糖协同激活的机制之间也发现了明显差异，即γ干扰素预处理并由脂多糖触发的巨噬细胞产生肿瘤坏死因子（TNF）和一氧化氮（NO），而MIF预处理的细胞则不产生。用γ干扰素预处理并由重组人TNF触发的巨噬细胞迁移受到抑制，而MIF未能与重组人TNF协同介导MMI。一氧化氮产生抑制剂NG-单甲基-L-精氨酸可抑制由较高激活浓度的脂多糖以及由γ干扰素预处理并由脂多糖触发的巨噬细胞介导的MMI，但对与脂多糖协同作用的MIF预处理细胞增加TNF-α mRNA和一氧化氮合酶mRNA的表达没有影响。综上所述，我们的结果表明，MIF和γ干扰素均可预处理巨噬细胞，使其与脂多糖协同介导MMI，但机制不同。γ干扰素介导迁移抑制的激活过程似乎类似于使巨噬细胞产生肿瘤细胞毒性的要求，即在预处理的巨噬细胞自分泌介导的一氧化氮生成过程中产生TNF。相比之下，MIF介导的MMI与TNF或NO的产生无关。
