The immunoregulatory C-C chemokine, macrophage inflammatory protein-1α (MIP-1α) has suppressive activity on proliferation of stem cells and early subsets of myeloid progenitor cells. A receptor for C-C chemokines that binds MIP-1α has been characterized, cloned, and shown to be related structurally to neuropeptide receptors that couple through G-proteins to phospholipase-C and adenyl cyclase. Yet, very little information on the intracellular mechanisms of action of MIP-1α is available. We show here that the human factor-dependent cell line M07e is responsive to the cell cycle-suppressive effects of MIP-1α, has specific membrane-binding sites for MIP-1α, and that treatment of these cells with this chemokine increases the phosphatidylcholine (PC) and phosphocholine turnover rates in cells that are synergistically stimulated by the combination of granulocyte-macrophage colony-stimulating factor and steel factor but not by these factors acting singly. Additionally, MIP-1α treatment induces a dose- and time-dependent increase in intracellular cAMP levels in M07e cells. Both exogenous PC and dibutyryl cAMP were found to suppress the proliferation of M07e colony-forming cells to a level similar to that of MIP-1α, further implicating cAMP and PC metabolism in MIP-1α-induced M07e suppression. RANTES, a related chemokine, with weak or incomplete binding to the cloned MIP-1α receptor, did not suppress M07e colony-forming cells, nor did it increase intracellular cAMP levels, but it did enhance growth factor-induced PC turnover, further supporting the involvement of cAMP in MIP-1α suppression while demonstrating that increased PC turnover alone is not sufficient for suppression. These findings support the idea that the human MIP-1α receptor is coupled to phospholipid and cAMP metabolism in a manner similar to other 7-transmembrane, G-protein-linked receptors and suggest that a phosphatidylcholine hydrolytic cycle and an associated increase in cAMP are part of the mechanisms of action of MIP-1α.
|Original language||English (US)|
|Number of pages||9|
|Journal||Journal of Immunology|
|State||Published - 1995|
ASJC Scopus subject areas
- Immunology and Allergy