Smith M E, van der Maesen K, Somera F P
Department of Neurology, VA Health Care System, Palo Alto, California, USA.
J Neurosci Res. 1998 Oct 1;54(1):68-78. doi: 10.1002/(SICI)1097-4547(19981001)54:1<68::AID-JNR8>3.0.CO;2-F.
Certain cytokines are believed to play a key role in the development of autoimmune demyelinating diseases. Little is known, however, about the effects of these cytokines in the regulation of the key event in myelin destruction, the phagocytosis of myelin by phagocytic cells. We investigated the effects of certain cytokines and growth factors on cultured peritoneal macrophages and microglia in respect to their various functions, phagocytosis, secreted proteolytic activity, and oxidative activity. Interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and lipopolysaccharide (LPS), all proinflammatory factors, actually decreased (IFN-gamma and LPS), or had no effect (TNF-alpha) on myelin phagocytosis by macrophages, but substantially increased phagocytic activity by microglia. Surprisingly, interleukins 4 and 10 (IL-4 and IL-10), considered to be downregulating cytokines, increased phagocytic activity by macrophages, while with microglia, IL-4 had no effect, but IL-10 almost doubled myelin phagocytosis. Transforming growth factor-beta (TGF-beta) had no significant effect on either cell. These cytokines did not affect proteolytic secretion in microglia, while IFN-gamma and LPS induced a doubling of the secreted proteases. This proteolytic activity was almost completely suppressed by calpain inhibitors, although some gelatinase appeared to be present. Microglia exerted much more oxidative activity on the membranes than macrophages, and granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin 1beta (IL-1beta) significantly increased microglial oxidative activity. The pattern of responses of macrophages and microglia to the cytokine types indicate that in cytokine-driven autoimmune demyelinating disease, microglia may be the more aggressive cell in causing tissue injury by phagocytosis and oxidative injury, while infiltrating macrophages may produce most of the proteolytic activity thought to contribute to myelin destruction.
某些细胞因子被认为在自身免疫性脱髓鞘疾病的发展中起关键作用。然而，关于这些细胞因子在髓鞘破坏的关键事件（即吞噬细胞对髓鞘的吞噬作用）调控中的作用，人们所知甚少。我们研究了某些细胞因子和生长因子对培养的腹膜巨噬细胞和小胶质细胞的各种功能、吞噬作用、分泌的蛋白水解活性和氧化活性的影响。干扰素-γ（IFN-γ）、肿瘤坏死因子-α（TNF-α）和脂多糖（LPS），所有这些促炎因子，实际上降低了（IFN-γ和LPS）或对巨噬细胞的髓鞘吞噬作用没有影响（TNF-α），但显著增加了小胶质细胞的吞噬活性。令人惊讶的是，白细胞介素4和10（IL-4和IL-10），被认为是下调细胞因子，增加了巨噬细胞的吞噬活性，而对于小胶质细胞，IL-4没有影响，但IL-10使髓鞘吞噬作用几乎增加了一倍。转化生长因子-β（TGF-β）对这两种细胞均无显著影响。这些细胞因子不影响小胶质细胞的蛋白水解分泌，而IFN-γ和LPS诱导分泌的蛋白酶增加了一倍。尽管存在一些明胶酶，但钙蛋白酶抑制剂几乎完全抑制了这种蛋白水解活性。小胶质细胞对膜的氧化活性比巨噬细胞强得多，粒细胞-巨噬细胞集落刺激因子（GM-CSF）和白细胞介素1β（IL-1β）显著增加了小胶质细胞的氧化活性。巨噬细胞和小胶质细胞对细胞因子类型的反应模式表明，在细胞因子驱动的自身免疫性脱髓鞘疾病中，小胶质细胞可能是通过吞噬作用和氧化损伤导致组织损伤的更具侵袭性的细胞，而浸润的巨噬细胞可能产生大部分被认为有助于髓鞘破坏的蛋白水解活性。
