Modulation of Fc gamma receptors on human mononuclear phagocytes by dexamethasone and interferon-gamma

Human monocytes and macrophages bear three distinct classes of cell surface receptors for the Fc portion of IgG, Fc$\sb{\gamma}$RI (CD64), Fc$\sb{\gamma}$RII (CD32), and Fc$\sb{\gamma}$RIII (CD16). These receptors mediate the removal of opsonized cells and immune complexes from the circulation and are thereby involved in the pathogenesis of several autoimmune diseases. We studied the modulation of these receptors on monocytes and the monocyte-like cell line, U937. We utilized the cytokine interferon-$\gamma$ and the synthetic glucocorticoid dexamethasone as model physiologic and pharmacologic signals, respectively. The modulation of Fc$\sb{\gamma}$RI and Fc$\sb{\gamma}$RII by these signals was examined at three levels: (a) protein expression on the cell surface; (b) amount of Fc$\sb{\gamma}$ receptor mRNA present; and (c) transcriptional rate of Fc$\sb{\gamma}$ receptor genes. We found that interferon-$\gamma$ increased protein expression and mRNA levels of Fc$\sb{\gamma}$RI on monocytes and Fc$\sb{\gamma}$RI and Fc$\sb{\gamma}$RII on U937 cells. In U937 cells, this modulation was due to increased gene transcription and not to alteration in mRNA stability. Dexamethasone treatment of U937 cells was observed to decrease the expression of Fc$\sb{\gamma}$RI and Fc$\sb{\gamma}$RII protein and the amount of Fc$\sb{\gamma}$RI mRNA without affecting the half-life of the transcript. Dexamethasone alone did not significantly affect protein expression or mRNA levels in monocytes. In U937 cells, treatment with both dexamethasone and interferon-$\gamma$ resulted in an inhibition of the increase in Fc$\sb{\gamma}$RI and Fc$\sb{\gamma}$RI mRNA and protein observed with interferon-$\gamma$. In contrast, in monocytes, treatment with both agents resulted in an augmentation of the interferon-$\gamma$-induced increase in Fc$\sb{\gamma}$RI mRNA and protein. In summary, we have found that Fc$\sb{\gamma}$ receptors on human mononuclear phagocytes are modulated by dexamethasone and interferon-$\gamma$ in a cell- and receptor-specific fashion. This modulation is due at least in part to changes in Fc$\sb{\gamma}$ receptor mRNA levels without alteration in mRNA stability. Further, we have specifically shown that interferon-$\gamma$ increased the transcription of the Fc$\sb{\gamma}$ receptor genes. Thus, these studies have explored the mechanism of regulation of this important group of receptors by two modulatory signals