人巨噬细胞刺激蛋白的生化特性、抗炎作用和分子机理

Human macrophage-stimulating protein:biochemical properties,antiinflammatory activities,and molecular mechanisms

巨噬细胞刺激蛋白(macrophage-stimulating protein,MSP),又称肝细胞生长因子样蛋白,是肝脏合成的一种具有免疫调节活性的糖蛋白。MSP以无生物学活性的单链蛋白前体的形式存在于血浆中。在炎症反应过程中,MSP前体经胰酶样丝氨酸蛋白酶和多种凝血酶激活,成为由α/β异二聚体构成的成熟MSP。MSP通过激活巨噬细胞膜上的特异性受体酪氨酸蛋白激酶RON而发挥其双重的炎症调节功能,既促进巨噬细胞的黏附、变形、移行和吞噬作用,又抑制巨噬细胞释放的多种炎症介质,如一氧化氮(NO)、前列腺素E2和一些细胞因子,从而达到清除病原体,控制炎症反应强度和促进组织修复的目的。MSP发挥其生物学功能的分子基础是它能够调节巨噬细胞内多条信号转导通路。因此,MSP在固有免疫、适应性免疫以及自身免疫性炎症反应中具有重要的抗炎作用。采用生物和药理学方式特异地激活MSP,可能在抑制炎症反应强度和减轻组织损伤中具有潜在的临床使用价值。

Macrophage-stimulating protein （MSP）, also known as hepatocyte growth factor-like protein, is a hepatocyte-produced protein possessing immunoregulatory activities. MSP is present in plasma as a biologically inactive single-chain precursor. During inflammation, pro-MSP is proteolytically converted into biologically active and mature α/β chain heterodimeric protein. Trypsin-like serine proteases and several enzymes from the blood coagulation systems are responsible for pro-MSP activation. By binding to its specific receptor tyrosine kinase RON, MSP exerts its dual immunoregulatory activities on tissue macrophages： stimulating macrophage adherence, shape change, migration and phagocytosis; and simultaneously, inhibiting various inflammatory mediators produced by macrophages such as inducible nitric oxide, prostaglandin E2 and several cytokines. These activities facilitate the body to eliminate invading pathogens, to control the intensity of inflammatory reactions, and to promote tissue repairing and wound healing. The molecular basis for MSP＇s functions relies on modulation of multiple signaling pathways in inflammatory macrophages. Thus, MSP plays an important role in regulate inflammatory reactions occurred during innate, adaptive and autoimmune responses. By regulating its activities through biological and pharmaceutical means, MSP could have clinical application potentials for minimizing tissue damages caused by uncontrolled inflammatory reactions.