INTERLEUKIN-1 INCREASES VACUOLAR-TYPE H-ATPASE ACTIVITY IN MURINE PERITONEAL-MACROPHAGES()

Maintenance of cytoplasmic pH (pH(i)) within a narrow physiological ra nge is crucial to normal cellular function. This is of particular rele vance to phagocytic cells within the acidic inflammatory microenvironm ent where the pH(i) tends to be acid loaded. We have previously report ed that a vacuolar-type H+-ATPase (V-ATPase) situated in the plasma me mbrane of macrophages and poised to extrude protons from the cytoplasm ic to the extracellular space is an important pH(i) regulatory mechani sm within the inflammatory milieu, Since this microenvironment is freq uently characterized by the influx of cells known to release inflammat ory cytokines, we performed studies to examine the effect of one such mediator molecule, interleukin-1 (IL-1), on pH(i) regulation in perito neal macrophages. IL-1 caused a time- and dose-dependent increase in m acrophage pH(i) recovery from an acute acid load. This effect was spec ific to IL-1 and was due to enhanced plasmalemmal V-ATPase activity. T he increased V-ATPase activity by IL-1 occurred following a lag period of several hours and required de novo protein and mRNA synthesis. How ever, Northern blot analysis revealed that IL-1 did not exert its effe ct via alterations in the levels of mRNA transcripts for the A or B su bunits of the V-ATPase complex, Finally, stimulation of both cAMP-depe ndent protein kinase and protein kinase C was required for the stimula tory effect of IL-1 on V-ATPase activity. Thus, cytokines present with in the inflammatory milieu are able to modulate pH(i) regulatory mecha nisms. These data may represent a novel mechanism whereby cytokines ma y improve cellular function at inflammatory sites.