Chronic hypoxia upregulates the expression and function of proinflammatory cytokines in the rat carotid body

Abstract

The structure and function of the carotid body are greatly altered during chronic hypoxia. Recent studies showed the expression of interleukin (IL)-1 receptor and IL-6 receptor in the carotid body, suggesting a role of proinflammatory cytokines in the chemoreceptor function. The present study aimed to examine the hypothesis that the expression of pro-inflammatory cytokines, namely IL-1beta, IL-6 and tumor necrosis factor (TNF)alpha, plays a role in the rat carotid body in chronic hypoxia. Levels of the mRNA expression of the cytokines and their receptors IL-1r1, gp130 and TNFr1, were significantly increased in the carotid body of hypoxic rats when compared with the normoxic control. Immunohistochemistry showed that the expressions of cytokines and receptors were localized in the lobules of chemosensitive glomus cells containing tyrosine hydroxylase. There were significantly more positive-staining cells in the hypoxic groups with treatment for 3, 7 and 28 days than those of the normoxic controls. Application of exogenous cytokines (0.1 nM) elevated intracellular calcium ([Ca(2+)](i)) responses to acute hypoxia in the dissociated fura-2-loaded glomus cells. The increased [Ca(2+)](i) response in the hypoxic group was significantly greater than that of the normoxic group. Moreover, the gene transcripts of inflammatory mediator inducible nitric oxide synthase and chemokines (MCP-1, CCR2, MIP-1alpha, and ICAM-1) were increased in the carotid body of hypoxic rats. Collectively, results suggest that the increased expressions of proinflammatory cytokines play a functional role in the carotid body with local inflammation during chronic hypoxia.