Complementary anti-inflammatory actions of the β2-adrenoceptor agonist clenbuterol and the glucocorticoid dexamethasone in rat brain

Systemic administration of the beta(2)-adrenoceptor agonist clenbuterol induces expression of IL-1 beta and its negative regulators, interleulcin-1 receptor antagonist (IL-1ra) and the interleukin-1 type II decoy receptor (IL-1RII) in rat brain. Clenbuterol also increases central expression of the broad spectrum anti-inflammatory cytokine interleukin-10 (IL-10) and its downstream signalling molecule, suppressor of cytokine signalling-3 (SOCS-3). Here we examine the impact of combined treatment with clenbuterol (05 mg/kg) and the glucocorticoid dexamethasone (1 mg/kg) on mRNA expression of IL-1 beta and the IL-1 beta-inducible gene iNOS, on I kappa B alpha mRNA expression and NF kappa B activation, and on mRNA expression of the anti-inflammatory molecules IL-Ira, IL-1RII, IL-10 and SOCS-3 in rat cortex, striatum and hippocampus. Dexamethasone inhibited induction of IL-1 beta and iNOS mRNA expression by clenbuterol in all three brain regions, without altering its ability to induce IL-1ra mRNA expression. In the case of IL-1RII, dexamethasone further augmented clenbuterol-induced IL-1RII mRNA expression in hippocampus and striatum. These data highlight a mechanistic dissociation between the ability of beta(2)-adrenoceptor activation to induce expression of IL-1 beta, and its negative regulators IL-1ra and IL-1RII in the brain. Treatment with either dexamethasone or clenbuterol alone independently induced I kappa B alpha mRNA expression, and elicited a concomitant decrease in the DNA binding of NF kappa B in all three brain regions. In the hippocampus and striatum dexamethasone treatment did not influence the ability of clenbuterol to induce IL-10 mRNA expression. In contrast in the cortex, induction of IL-10 and SOCS-3 mRNA expression by clenbuterol administered in combination with dexamethasone was less than induced by clenbuterol alone. Overall these data indicate that combined treatment with dexamethasone and the beta(2)-adrenoceptor agonist clenbuterol elicit complementary anti-inflammatory actions in the CNS. Specifically, dexamethasone inhibits expression of pro-inflammatory cytokines, whereas clenbuterol has the added benefit of promoting expression of anti-inflammatory molecules including IL-1ra, 1L-1RII, IL-10 and SOCS-3. (C) 2010 Elsevier B.V. All rights reserved.