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Background  The NF-κB signaling pathway orchestrates many of the intricate aspects of neuroinflammation. Astrocytic β 2 -adrenergic receptors have emerged as potential regulators in central nervous system inflammation and are potential targets for pharmacological modulation. The aim of this study was to elucidate the crosstalk between astrocytic β 2 -adrenergic receptors and the TNF-α induced inflammatory gene program.    Methods  Proinflammatory conditions were generated by the administration of TNF-α. Genes that are susceptible to astrocytic crosstalk between β 2 -adrenergic receptors (stimulated by clenbuterol) and TNF-α were identified by qPCR-macroarray-based gene expression analysis in a human 1321 N1 astrocytoma cell line. Transcriptional patterns of the identified genes  in vitro  were validated by RT-PCR on the 1321 N1 cell line as well as on primary rat astrocytes.  In vivo  expression patterns were examined by intracerebroventricular administration of clenbuterol and/or TNF-α in rats. To examine the impact on the inflammatory cell content of the brain we performed extensive FACS analysis of rat brain immune cells after intracerebroventricular clenbuterol and/or TNF-α administration.    Results  Parallel transcriptional patterns  in vivo  and  in vitro  confirmed the relevance of astrocytic β 2 -adrenergic receptors as modulators of brain inflammatory responses. Importantly, we observed pronounced effects of β 2 -adrenergic receptor agonists and TNF-α on IL-6, CXCL2, CXCL3, VCAM1, and ICAM1 expression, suggesting a role in inflammatory brain cell homeostasis. Extensive FACS-analysis of inflammatory cell content in the brain demonstrated that clenbuterol/TNF-α co-administration skewed the T cell population towards a double negative phenotype and induced a shift in the myeloid brain cell population towards a neutrophilic predominance.    Conclusions  Our results show that astrocytic β 2 -adrenergic receptors are potent regulators of astrocytic TNF-α-activated genes  in vitro  and  in vivo , and ultimately modulate the molecular network involved in the homeostasis of inflammatory cells in the central nervous system. Astrocytic β 2 -adrenergic receptors and their downstream signaling pathway may serve as potential targets to modulate neuroinflammatory responses.

β2-adrenergic agonists modulate TNF-α induced astrocytic inflammatory gene expression and brain inflammatory cell populations