Regulation of interleukin‐10 production by β‐adrenergic agonists

Abstract

Catecholamines have been shown to inhibit some aspects of macrophage activation through a beta receptor-dependent mechanism. This study was undertaken to analyze the effects of isoproterenol, a specific beta-adrenergic agonist, on the synthesis of interleukin-10 (IL-10), a major macrophage-deactivating factor. Isoproterenol increased IL-10 release from lipopolysaccharide-(LPS)-activated mouse peritoneal macrophages in a dose-dependent manner. A significant effect was already observed with 1 microM isoproterenol, while a 4.5-fold increase was achieved with 10 microM. This increase was observed only if macrophages were exposed to isoproterenol for at least 2 h before LPS challenge. It was apparent within 0.5 h and persisted through 24 h at all the LPS concentrations used. A similar increase was observed at the IL-10 mRNA level, as judged by enzyme-linked immunosorbent assay-polymerase chain reaction. The macrophage response to isoproterenol that led to cyclic AMP accumulation was markedly inhibited by H-89, a potent inhibitor of protein kinase A. These data suggest the involvement of cyclic AMP in the regulation of IL-10 synthesis by isoproterenol. IL-10 was in turn partly responsible for a reduction in tumor necrosis factor-alpha synthesis. In vivo, the administration of oxprenolol, a beta-receptor antagonist, significantly reduced serum IL-10 levels 90 min after LPS challenge. Thus, the present study provides the first evidence that endogenous catecholamines are of critical importance in determining the magnitude of the IL-10 response in experimental endotoxemia.

Adrenergic modulation of splenic macrophage cytokine release in polymicrobial sepsis

“…Although our observed lack of effect of IL-10 to attenuate proinflammatory cytokine release is in contrast to previous works, suggesting their physiological actions (37,38), the critical in vivo concentration determining this effect is not known. It can be argued that our ex vivo culture conditions may not accurately represent the in vivo milieu.…”

“…Monocytes have been demonstrated to release IL-10 in response to adrenergic stimulation (45), and this response is greatly augmented in the presence of bacterial endotoxin (37,38). TNF-␣ and IL-6 release in whole blood, presumably by monocytic cells, has been shown to be inhibited by catecholamines (4,41,42), and similar results were found with the use of a monocytic cell line (35).…”

Salmeterol, a β2-receptor agonist, attenuates lipopolysaccharide-induced lung inflammation in mice

“…Indeed, ␤-receptor agonists potently inhibited the production of TNF-␣ by monocytes in vitro and in mice and normal humans in vivo (5,32,33,38,42,46). In addition, ␤-receptor stimulation resulted in an enhanced release of the anti-inflammatory cytokine IL-10 in these models (36,38,42,46). In mice, salmeterol attenuated TNF-␣ release after systemic administration of LPS, which was associated with an improved survival in galactosamine-sensitized mice (32).…”

Dual Ligand Stimulation of RAW 264.7 Cells Uncovers Feedback Mechanisms That Regulate TLR-Mediated Gene Expression

“…Several substances elevating intracellular cAMP levels including PGE 2 and ISO have been reported to enhance LPS-induced IL-10 gene expression (86,87,(93)(94)(95)(96)(97)(98)(99)(100)(101). It is possible that intracellular cAMP activates protein kinase A, which in turn phosphorylates CREB, and the phosphorylated CREB contributes to the enhancement of LPS-induced IL-10 transcription.…”