Orens J B, Lukacs N W, Kunkel S L, Burdick M D, Wilke C A, Walz A, Strieter R M
Department of Medicine, University of Michigan, Ann Arbor.
Cell Immunol. 1994 Jun;156(1):95-101. doi: 10.1006/cimm.1994.1155.
Previous studies have shown that during the development of a mixed lymphocyte reaction (MLR) levels of the chemotactic cytokines IL-8 and MCP-1 (members of the C-X-C and C-C supergene families, respectively) increase in a time-dependent fashion, and that the production of these chemokines correlates with the magnitude of responsiveness to alloantigen. Furthermore, the responsiveness to alloantigen in the context of a MLR has been shown to be regulated by the oxidative metabolism of L-arginine. We postulated that competitive antagonism of the L-arginine metabolic pathway in a human MLR may alter the production of members of the C-C and C-X-C chemokine families. To test this hypothesis, mononuclear cells were isolated from healthy individuals and subjected to a one-way MLR in the presence or absence of varying concentrations of an L-arginine competitive inhibitor, NG-methyl-L-arginine (NMA: 50 to 500 microM). When the MLR was performed in the presence of NMA (500 microM), the production of IL-8 increased twofold (P < 0.05) and ENA-78 increased fivefold (P < 0.05), while MCP-1 and MIP-1 alpha were not significantly altered. These findings suggest that NMA, an inhibitor of the L-arginine metabolic pathway, may regulate the production of specific C-X-C chemokines, IL-8 and ENA-78, during a MLR. In contrast, the production of MCP-1 and MIP-1 alpha, members of the C-C chemokine family, does not appear to be regulated by this inhibitor of the oxidative metabolism of L-arginine in the context of a MLR.
先前的研究表明，在混合淋巴细胞反应（MLR）的发展过程中，趋化细胞因子IL-8和MCP-1（分别为C-X-C和C-C超基因家族的成员）的水平呈时间依赖性增加，并且这些趋化因子的产生与对同种异体抗原的反应强度相关。此外，在MLR背景下对同种异体抗原的反应性已被证明受L-精氨酸氧化代谢的调节。我们推测，在人类MLR中L-精氨酸代谢途径的竞争性拮抗作用可能会改变C-C和C-X-C趋化因子家族成员的产生。为了验证这一假设，从健康个体中分离出单核细胞，并在存在或不存在不同浓度的L-精氨酸竞争性抑制剂NG-甲基-L-精氨酸（NMA：50至500μM）的情况下进行单向MLR。当在NMA（500μM）存在下进行MLR时，IL-8的产生增加了两倍（P <0.05），ENA-78增加了五倍（P <0.05），而MCP-1和MIP-1α没有明显改变。这些发现表明，NMA作为L-精氨酸代谢途径的抑制剂，可能在MLR过程中调节特定的C-X-C趋化因子IL-8和ENA-78的产生。相比之下，在MLR背景下，C-C趋化因子家族成员MCP-1和MIP-1α的产生似乎不受这种L-精氨酸氧化代谢抑制剂的调节。
