Modulation of interleukin-6 by beta(2)-adrenoceptor in endotoxin-stimulated renal macrophage cells

Background. Activation of the cAMP signaling pathway by means of beta(2)-ad renoceptor agonists has been shown to up-regulates interleukin-6 (IL-6) gen e expression and to stimulate IL-6 production in macrophage cells. However, whether beta(2)-adrenoceptor activation can also modify the rate of IL-6 p roduction in macrophage cells activated by the bacterial endotoxins has not yet been determined. Using renal resident macrophage cells treated with en dotoxin, lipopolysaccharide (LPS), and beta(2)-adrenoceptor agonist, terbut aline, we investigated the role of cAMP pathway, tumor necrosis factor (TNF )-alpha and mitogen-activated protein kinase (MAPK) pathway (p42/p44) in re gulating IL-6 production. Methods. IL-6 protein. mRNA, and promoter activity were measured in these c ells exposed to LPS (1 mu g/ml) and/or terbutaline (10(-9) to 10(-6) M). Fu rthermore, the time course effects of terbutaline on cAMP, MAPK (p42/p44). and TNF-alpha release were evaluated in the cells. Results. Terbutaline at high concentrations (10(-6) M) significantly up-reg ulated IL-6 by approximately 25% (P < 0.05), whereas at a lower concentrati on (10(-8) M), it down-regulated IL-6 production by 42% (P < 0.05), Terbuta line (10(-8) and 10(-6) M) caused a concentration- and time-dependent stimu lation of cAMP (P < 0.05) and TNF production (P < 0.05) and a time dependen t decrease in MAPK activity (P < 0.05). Following the addition of a cAMP in hibitor, IL-6 promoter activity was correlated with TNF-alpha levels and MA PK activity. Conclusions. A biphasic effect of beta(2)-adrenoceptor agonist on IL-6 prod uction in renal resident macrophage cells became apparent when LPS was expo sed to the cells. The terbutaline-induced down-regulation of IL-6 gene prod uction was mediated by an inhibitory effect of terbutaline on TNF-alpha, wh ich was exerted through the MAPK and cAMP pathways, whereas the up-regulati on appeared to be due to a direct action of intracellular cAMP.