Abstract 484: Acidic pH Triggers Secretion of Proinflammatory Cytokines in Human Macrophages

Abstract

Extracellular acidification can occur in atherosclerotic lesions, specifically in areas with high numbers of metabolically active macrophages secreting lactate and hydrogen ions. There is a growing body of evidence showing that acidification of the extracellular environment causes fundamental changes in the functions of immune cells. Here we studied the effect of low pH on the secretion of proinflammatory cytokines by cultured human macrophages. Using custom manufactured cell culture media with neutral and acidic pH (pH 7.5-6.0) we discovered that acidic pH triggers secretion of interleukin(IL)-1beta and IL-18, but not of IL-1alpha. IL-1beta and IL-18 are both produced as proforms that are processed into the biologically active secreted form by the caspase-1 protease. The IL-1beta secretion induced by acidic pH was paralleled by caspase-1 activation, and inhibition of caspase-1 completely abolished IL-1beta secretion. Acidic pH-induced IL-1beta secretion was also abolished at high extracellular potassium concentrations, which implies that potassium efflux from cells is a crucial step upstream of caspase-1 activation. We are currently exploring the involvement of inflammasomes in the acidic pH -induced caspase-1 activation. In conclusion, acidic microenvironments of atherosclerotic lesions may induce proinflammatory cytokine secretion in macrophages, so amplifying the progression of atherogenesis.