IFN-gamma is critical to the control of murine autoimmune encephalomyelitis and regulates both in the periphery and in the target tissue: a possible role for nitric oxide.
IFN-gamma is critical to the control of murine autoimmune encephalomyelitis and regulates both in the periphery and in the target tissue: a possible role for nitric oxide.
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发表时间：
1999-11
影响因子：
4.4
通讯作者：
D. Willenborg;S. Fordham;M. Staykova;I. Ramshaw;William B. Cowden
中科院分区：
文献类型：
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作者：
D. Willenborg;S. Fordham;M. Staykova;I. Ramshaw;William B. Cowden
在中枢神经系统炎性疾病自身免疫性脑脊髓炎（EAE）的背景下，NO和IFN-γ通常分别被认为是细胞毒性和促炎分子。使用缺乏IFN-γ受体的配体结合链（IFN-γ R-/-）的小鼠，我们先前已经表明IFN-γ对于髓鞘少突胶质细胞糖蛋白肽（MOG 35 -55）诱导的EAE表达不是必需的，但实际上对于其下调是必需的。在这里，我们研究了IFN-γ调节的下游分子和细胞机制，并证明IL-4和IL-10似乎都没有在下调中发挥作用，各种淋巴细胞群也没有。巨噬细胞谱系的细胞是下调的关键，如来自IFN γ R +/+小鼠的腹膜渗出液细胞抑制Ag驱动的IFN γ R-/-淋巴细胞增殖而IFN γ R-/-腹膜渗出液细胞不抑制的事实所证明的。在前一种培养物中检测到高水平的活性氮中间产物，但在后一种培养物中检测不到，并且诱导型NO合酶抑制剂对增殖的抑制是可逆的，这表明NO在下调中发挥关键作用。骨髓嵌合体的研究表明，下调不仅发生在全身，而且在靶组织内。这些数据表明，IFN-γ通过诱导诱导型NO合酶和随后的NO产生来下调EAE，这两者都是由外周中的巨噬细胞和通过推断靶组织中的小胶质细胞和星形胶质细胞引起的。
NO and IFN-gamma have normally been considered cytotoxic and proinflammatory molecules, respectively, in the setting of the central nervous system inflammatory disease autoimmune encephalomyelitis (EAE). Using mice lacking the ligand binding chain of the IFN-gamma receptor (IFNgammaR-/-), we have previously shown that IFN-gamma is not essential for myelin oligodendrocyte glycoprotein peptide (MOG35-55) induced EAE expression but is in fact essential for its down-regulation. Here we examined the downstream molecular and cellular mechanism(s) of IFN-gamma regulation and demonstrate that neither IL-4 nor IL-10 appear to play a role in down-regulation nor do various lymphoid cell populations. Cells of the macrophage lineage are key to down-regulation as evidenced by the fact that peritoneal exudate cells from IFNgammaR+/+ mice inhibit Ag-driven proliferation of IFNgammaR-/- lymphocytes, whereas IFNgammaR-/- peritoneal exudate cells do not. High levels of reactive nitrogen intermediates are detected in the former cultures but not the latter, and the inhibition of proliferation is reversible with an inhibitor of inducible NO synthase, indicating a key role for NO in down-regulation. Studies with bone marrow chimeras indicate that down-regulation occurs not only systemically but also within the target tissue. These data suggest that IFN-gamma down-regulates EAE by inducing inducible NO synthase and subsequently NO production, both by macrophages in the periphery and, by inference, microglia and astrocytes in the target tissue.