Induction of the Chemokine β Peptides, MIP-1α and MIP-1β, by Lipopolysaccharide Is Differentially Regulated by Immunomodulatory Cytokines γ-IFN, IL-10, IL-4, and TGF-β

The macrophage occupies a central role in the host response to invasion, exerting its control over the developing inflammatory response largely through the elaboration of an assortment of endogenous mediators including many cytokines. The β chemokine peptides, macrophage inflammatory protein [MIP]-1α and MIP-1β, are two such effectors markedly up-regulated in macrophages following exposure to bacterial lipopolysaccharide (LPS). These highly homologous peptides, like the other members of the β chemokine family, exhibit diverse but partially overlapping biological activity profiles, suggesting that the cellular participants and intensity of an inflammatory response may in part be regulated by selective expression of these chemokines. Studies reported here demonstrate that, in contrast to the “balanced” MIP-1α/MIP-1β chemokine responses of LPS-stimulated macrophage cultures in vitro, circulating levels of MIP-1β are significantly higher than those of MIP-1α 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 stimulus (γ-IFN, IL10, IL-4, and transforming growth factor [TGF]-β) down-regulated the LPS-induced release of MIP-1α by macrophages in vitro, but spared the MIP-1β response. This altered pattern of secretion may explain, at least in part, the high circulating levels of MIP-1β relative to MIP-1α observed in vivo in response to LPS challenge.