Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei X F, Achong M K
Immunology and Infection Program, Department of Pathology, McMaster University, Hamilton, Ontario, L8N 3Z5 Canada.
J Clin Invest. 1998 Jan 15;101(2):311-20. doi: 10.1172/JCI1368.
IL-6 is induced often together with the proinflammatory cytokines TNFalpha and IL-1 in many alarm conditions, and circulating IL-6 plays an important role in the induction of acute phase reactions. However, whether this endogenous IL-6 plays any additional pro- or antiinflammatory roles in local or systemic responses remains unclear. In this study, the role of IL-6 in acute inflammatory responses was investigated in animal models of endotoxic lung or endotoxemia by using IL-6+/+ and IL-6-/- mice. Aerosol exposure of endotoxin induced increased IL-6 and proinflammatory cytokines TNFalpha and MIP-2 and a neutrophilic response in the lung of IL-6+/+ mice. However, the levels of TNFalpha and MIP-2 and neutrophilia were significantly higher in the lung of IL-6-/- mice. The rate of neutrophil apoptosis in these mice was similar to that in IL-6+/+ mice. A low constitutive level of antiinflammatory cytokine IL-10 was not enhanced by endotoxin and remained similar in the lung in both IL-6+/+ and IL-6-/- mice. Systemically, intraperitoneal delivery of endotoxin resulted in much more pronounced circulating levels of TNFalpha, MIP-2, GM-CSF, and IFNgamma in IL-6-/- mice than in IL-6+/+ mice, and administration of recombinant IL-6 to IL-6-/- mice abolished these differences. In contrast, circulating IL-10 levels were induced to a similar degree in both IL-6+/+ and IL-6-/- mice. Thus, our studies reveal that endogenous IL-6 plays a crucial antiinflammatory role in both local and systemic acute inflammatory responses by controlling the level of proinflammatory, but not antiinflammatory, cytokines, and that these antiinflammatory activities by IL-6 cannot be compensated for by IL-10 or other IL-6 family members.
在许多应激状态下，白细胞介素-6（IL-6）常与促炎细胞因子肿瘤坏死因子α（TNFα）和白细胞介素-1共同被诱导产生，并且循环中的IL-6在急性期反应的诱导中发挥重要作用。然而，这种内源性IL-6在局部或全身反应中是否发挥任何额外的促炎或抗炎作用仍不清楚。在本研究中，通过使用IL-6+/+和IL-6-/-小鼠，在内毒素性肺或内毒素血症的动物模型中研究了IL-6在急性炎症反应中的作用。内毒素气溶胶暴露诱导IL-6+/+小鼠肺中IL-6、促炎细胞因子TNFα和巨噬细胞炎症蛋白-2（MIP-2）增加以及中性粒细胞反应。然而，IL-6-/-小鼠肺中TNFα和MIP-2的水平以及中性粒细胞增多明显更高。这些小鼠中性粒细胞凋亡率与IL-6+/+小鼠相似。抗炎细胞因子白细胞介素-10的基础水平较低，内毒素未使其升高，在IL-6+/+和IL-6-/-小鼠肺中均保持相似。在全身水平，腹腔注射内毒素导致IL-6-/-小鼠中TNFα、MIP-2、粒细胞-巨噬细胞集落刺激因子（GM-CSF）和干扰素γ（IFNγ）的循环水平比IL-6+/+小鼠中更显著，并且给IL-6-/-小鼠注射重组IL-6消除了这些差异。相反，IL-6+/+和IL-6-/-小鼠中循环IL-10水平诱导程度相似。因此，我们的研究表明，内源性IL-6通过控制促炎细胞因子而非抗炎细胞因子的水平，在局部和全身急性炎症反应中发挥关键的抗炎作用，并且IL-6的这些抗炎活性不能被IL-10或其他IL-6家族成员所补偿。
