Delgado Mario, Jonakait G Miller, Ganea Doina
Department of Biological Sciences, Rutgers University, Newark, New Jersey 07102, USA.
Glia. 2002 Aug;39(2):148-61. doi: 10.1002/glia.10098.
Microglia react to even minor disturbances in CNS homeostasis and function as critical regulators of CNS inflammation. Activated microglia secrete inflammatory mediators such as cytokines and chemokines, which contribute to the pathophysiological changes associated with several neuroimmunologic disorders. Microglia-derived inflammatory chemokines recruit various populations of immune cells, which initiate and maintain the inflammatory response against foreign antigens. Entry and retention of activated immune cells in the CNS is a common denominator in a variety of traumatic, ischemic, and degenerative diseases. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) are two structurally related neuropeptides that function as potent anti-inflammatory factors in the periphery. Here we investigated the effects of VIP and PACAP on chemokine production by activated microglia. VIP and PACAP inhibit the expression of the microglia-derived CXC chemokines MIP-2 and KC, and of the CC chemokines MIP-1alpha, -1beta, MCP-1, and RANTES. The inhibition of chemokine gene expression correlates with an inhibitory effect of VIP/PACAP on NFkB binding. The VIP/PACAP inhibition of both chemokine production and of NFkB binding is mediated through the specific receptor VPAC1 and involves a cAMP-dependent intracellular pathway. Of biological significance is the fact that the inhibition of chemokine production by VIP/PACAP leads to a significant reduction in the chemotactic activity generated by activated microglia for peripheral leukocytes, i.e., neutrophils, macrophages, and lymphocytes. Because reduction in the number and activation of infiltrating leukocytes represents an important factor in the control of inflammation in the CNS, VIP and/or PACAP released by neurons during an inflammatory response could serve as neuronal survival factors by limiting the inflammatory process.
小胶质细胞对中枢神经系统（CNS）内环境稳态的哪怕是轻微干扰都会产生反应，并作为CNS炎症的关键调节因子发挥作用。活化的小胶质细胞会分泌炎性介质，如细胞因子和趋化因子，这些介质会导致与多种神经免疫疾病相关的病理生理变化。小胶质细胞衍生的炎性趋化因子会募集各种免疫细胞群体，从而启动并维持针对外来抗原的炎症反应。活化免疫细胞进入并滞留于CNS是多种创伤性、缺血性和退行性疾病的一个共同特征。血管活性肠肽（VIP）和垂体腺苷酸环化酶激活多肽（PACAP）是两种结构相关的神经肽，它们在外周作为强效抗炎因子发挥作用。在此，我们研究了VIP和PACAP对活化小胶质细胞趋化因子产生的影响。VIP和PACAP可抑制小胶质细胞衍生的CXC趋化因子MIP-2和KC以及CC趋化因子MIP-1α、-1β、MCP-1和RANTES的表达。趋化因子基因表达的抑制与VIP/PACAP对NFkB结合的抑制作用相关。VIP/PACAP对趋化因子产生和NFkB结合的抑制是通过特异性受体VPAC1介导的，并且涉及一条cAMP依赖性细胞内途径。具有生物学意义的是，VIP/PACAP对趋化因子产生的抑制导致活化小胶质细胞对外周白细胞（即中性粒细胞、巨噬细胞和淋巴细胞）产生的趋化活性显著降低。由于浸润白细胞数量和活化的减少是控制CNS炎症的一个重要因素，因此在炎症反应期间由神经元释放的VIP和/或PACAP可通过限制炎症过程而作为神经元存活因子发挥作用。
