Desensitization of macrophages to stimuli which induce secretion of superoxide anion. Down-regulation of receptors for phorbol myristate acetate.
The ability of cultivated mouse peritoneal macrophages (M phi) to release superoxide anion (O-2) after repeated stimulation by phorbol myristate acetate (PMA) or serum-treated zymosan (STZ) has been studied. After a maximal first stimulus bacillus Calmette-Guérin (BCG)-activated M phi released high levels of O-2, 2-fold more than thioglycollate-elicited M phi and the response ceased within 4 h. Both populations either responded again to a second challenge or displayed a refractory state which varied in duration and selectivity. Desensitization by STZ pretreatment was transient and selective whereas PMA could render M phi refractory for 3 days to PMA alone or to both agents, depending on the amount of PMA used and the conditions of stimulation. PMA induced a selective loss of specific saturable receptors for [3H]phorbol dibutyrate, a closely related agent, and receptor activity recovered with the ability to release O-2. Loss of receptors did not account for concomitant loss of the response to STZ after nonselective deactivation. Such M phi were fully viable and able to endocytose various soluble and particulate ligands vigorously, but without stimulation of the hexose monophosphate shunt or release of O-2. Our studies indicate that M phi activities can be profoundly altered by prior stimulation, that specific receptors play a role in ligand-induced desensitization and that agents such as PMA can selectively eliminate the cells' ability to generate a second respiratory burst.
D000818:Animals; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D002448:Cell Adhesion; D002478:Cells, Cultured; D005260:Female; D008264:Macrophages / Q000502:physiology*; D008297:Male; D051379:Mice; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption; D010587:Phagocytosis; D011493:Protein Kinase C; D011956:Receptors, Cell Surface / Q000502:physiology*; D011955:Receptors, Drug; D013481:Superoxides / Q000378:metabolism*; D013997:Time Factors
D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D011956:Receptors, Cell Surface; D011955:Receptors, Drug; C083141:phorbol ester binding protein; C027776:phorbol ester receptor; D013481:Superoxides; D011493:Protein Kinase C; D010100:Oxygen