ID: 190: Adrenergic regulation of Interleukin-6 and chemokine expression: Stressing NF-kappaB

β 2-adrenergic receptor ( β 2-AR) agonists are widely applied in the clinic for treatment of respiratory disease. Although their therapeutic effect mainly results from their spasmolytic activity, β -agonists have also been attributed with anti-inflammatory properties. We studied the effect of β -agonist cotreatment on TNF- α -induced activation of inflammatory signalling in astrocytes, focusing on Nuclear Factor- κ B (NF- κ B), a master regulator of inflammatory gene expression. Unexpectedly, we observed that, unlike other anti-inflammatory drugs, β -agonists did not inhibit the activity of NF- κ B. Instead, β -agonist cotreatment enhanced TNF- α -induced expression of a subset of prototypical NF- κ B target genes. The most pronounced effect was apparent for Interleukin-6 (IL-6) and the CXC chemokines CXCL2 and CXCL3. We established that cooperativity between NF- κ B and β 2-AR-induced transcriptional regulators is at the basis of the synergy. Our current research aims at further defining the molecular players regulating IL-6 transcription using a novel approach combining DNA affinity purification and mass spectrometry. Importantly, the β 2-agonist-induced potentiation of inflammatory responses was also recapitulated in vivo , in rats treated intracerebroventricularly with a combination of TNF- α and clenbuterol. Gene expression changes were furthermore reflected in a redistribution of the leukocyte subsets present in the brain. More specifically, a skewing of the T-cell population towards a double-negative phenotype, and a shift towards neutrophilic expansion in the myeloid subset were apparent. Although functional characterization of the infiltrating leukocytes remains to be done, these results suggest β -agonists can catalyze inflammatory reactions in vivo and warrant further study into their mode of action.