HUMAN MONOCYTE CHEMOATTRACTANT PROTEIN (MCP)-4 IS A NOVEL CC CHEMOKINE WITH ACTIVITIES ON MONOCYTES, EOSINOPHILS, AND BASOPHILS INDUCED IN ALLERGIC AND NONALLERGIC INFLAMMATION THAT SIGNALS THROUGH THE CC CHEMOKINE RECEPTORS (CCR)-2 AND CCR-3

The chemokines are a large family of cytokines that regulate the compl ex and precise recruitment of immune cells into inflammatory foci. To fully appreciate their role in the pathogenesis of human diseases, the entire spectrum of chemokines, their receptors, their cellular target s, and mechanisms of regulation need to be delineated. Using eotaxin a s a probe, we isolated a cDNA for a novel human beta (or CC) chemokine that, based on its biological and structural features, we have named monocyte chemoattractant protein (MCP)-4. Purified recombinant MCP-4 p rotein was a potent chemoattractant for monocytes and eosinophils and stimulated histamine release from basophils. MCP-4 induced a calcium f lux in HEK-293 cells transfected with the monocyte selective MCP-1 rec eptor (CCR-2B) and the eosinophil selective eotaxin receptor (CCR-3), but not in the more widely expressed CCR-1 or CCR-5. This novel chemok ine is expressed in TNF-alpha and IL-1 activated epithelial and endoth elial cells in vitro, and in the epithelial mucosa of patients with bo th Th2-type allergic and Th1-type nonallergic sinusitis. Furthermore, both IFN-gamma and IL-4, products of Th1 and Th2 cells, respectively, synergized with TNF-alpha and IL-1 in inducing MCP-4 mRNA accumulation , These properties of MCP-4 offer a molecular explanation for the obse rved accumulation of monocytes, eosinophils and basophils in both Th1- and Th2-type immune responses.