Potentiation of interferon-γ-stimulated nitric oxide production by retinoic acid in RAW 264.7 cells

Nitric oxide (NO) production is essential for normal immunity. We have examined the capacity of retinoic acid (RA), a pleiotropic hormone necessary for normal immunity, to modulate NO production in RAW 264.7 cells. NO production induced by suboptimal concentrations of interferon-γ (IFN-γ) was significantly greater in cells cultured in low-retinoid medium and treated with all-trans-RA (10^-10 - 10^-6 M, P<0.05), as well as with 9-cis-RA and several retinoids selective for the RA receptor subfamily of nuclear retinoid receptors. Similar results were obtained with lipopolysaccharide and monophosphoryl lipid A as stimuli. The RA-potentiated production of NO was positively correlated with inducible NO synthase (iNOS) protein (r=0.94, P<0.002), although the expression of iNOS mRNA was not altered. We hypothesize that modulation of the macrophage response to suboptimal immune stimuli by physiological concentrations of RA, as observed in these studies, may be important in establishing an optimal balance between T helper (Th) 1- and Th2-mediated immunity.