INDUCTION OF THE CHEMOKINE-BETA PEPTIDES, MIP-1-ALPHA AND MIP-1-BETA,BY LIPOPOLYSACCHARIDE IS DIFFERENTIALLY REGULATED BY IMMUNOMODULATORYCYTOKINES GAMMA-IFN, IL-10, IL-4, AND TGF-BETA

The macrophage occupies a central role in the host response to invasio n, exerting its control over the developing inflammatory response larg ely through the elaboration of an assortment of endogenous mediators i ncluding many cytokines. The beta chemokine peptides, macrophage infla mmatory protein [MIP]-1 alpha and MIP-1 beta, are two such effecters m arkedly up-regulated in macrophages following exposure to bacterial li popolysaccharide (LPS). These highly homologous peptides, like the oth er members of the beta chemokine family, exhibit diverse but partially overlapping biological activity profiles, suggesting that the cellula r participants and intensity of an inflammatory response may in part b e regulated by selective expression of these chemokines. Studies repor ted here demonstrate that, in contrast to the ''balanced'' MIP-1 alpha /MIP-1 beta chemokine responses of LPS-stimulated macrophage cultures in vitro, circulating levels of MIP-1 beta are significantly higher th an those of MIP-1 alpha following LPS administration in vivo. Further studies have revealed that several immunomodulatory cytokines known to be up-regulated in vivo as a consequence of exposure to an invasive s timulus (gamma-IFN, IL-10, IL-4, and transforming growth factor [TGF]- beta) down-regulated the LPS-induced release of MIP-1 alpha by macroph ages in vitro, but spared the MIP-1 beta response. This altered patter n of secretion may explain, at least in part, the high circulating lev els of MIP-1 beta relative to MIP-1 alpha observed in vivo in response to LPS challenge.