Role of corticosterone and epinephrine on TNF and IL-6 production from isolated perfused rat liver and Kupffer cells.

Abstract

A bidirectional communication exists between the nervous system and the immune system. Rats injected with an inflammatory stimulus lipopolysaccharide (LPS) and exposed to psychological stress have elevations in circulating TNF and IL-6, however, the source of these cytokines is unknown. The experiments in this thesis were designed to test the hypothesis that the liver is an important organ in the production/release of TNF and IL-6 in response to LPS in in vivo, in situ and in vitro model systems, and that stress hormones (corticosterone and epinephrine) will alter this production from isolated perfused rat liver (IPRL) and Kupffer cells. LPS caused dose-dependent elevations in TNF and IL-6 secretion from IPRL. The Kupffer cells appeared to be the major source of TNF and IL-6 secreted from the liver. Studies with anisomycin, a protein-synthesis inhibitor, indicated that the secretion was dependent on protein synthesis. Corticosterone (both low and high doses in the physiological range from 35 to 350 ng/ml) alone increased TNF and IL-6 secretion from the IPRL. However, when LPS was combined with corticosterone, the lower dose of corticosterone facilitated this cytokine secretion, whereas the higher doses of corticosterone suppressed the cytokine secretion. Interestingly, when Kupffer cells were studied in vitro, both low and high physiological doses of corticosterone decreased LPS induced TNF and IL-6 secretion. Epinephrine (1 $\mu$M) alone significantly increased IL-6 secretion, but had no effect on TNF secretion from IPRL. This same dose of epinephrine significantly increased LPS-induced IL-6, but decreased LPS-induced TNF secretion. Both responses were inhibited by the $\beta$ adrenergic blocker propranolol. In studies from isolated Kupffer cells and hepatocytes, epinephrine significantly decreased LPS-induced TNF, but increased LPS-induced IL-6 secretion in Kupffer cells, consistent with our IPRL data. However, epinephrine alone had no effects on TNF and IL-6 production either in Kupffer cells or in hepatocytes. These data support the hypothesis that epinephrine can promote IL-6 secretion from the IPRL and Kupffer cells via $\beta$-receptor activation. In studies from rat monocytes, corticosterone significantly decreased LPS-induced TNF and IL-6 secretion at all examined doses (35, 350 and 3500 ng/ml). Epinephrine (1 $\mu$M) significantly increased LPS-induced TNF and IL-6 secretion and these effects were inhibited by the $\beta$ blocker propranolol (10 $\mu$M). Anisomycin (1 $\mu$M) completely blocked the elevation in TNF and IL-6 in the monocyte supernatants. Overall, these data are consistent with the hypotheses that corticosterone suppresses LPS-induced TNF and IL-6 secretion, and epinephrine elevates LPS-induced secretion of these cytokines. The effects of epinephrine on TNF and IL6 secretion are mediated by $\beta$-adrenergic receptors, and the secretion of these cytokines from rat monocytes is dependent on protein synthesis.