Key role of the sympathetic microenvironment for the interplay of TNF and IL-6 in normal but not in inflamed mouse colon mucosa

Rainer H Straub ^1*, Katrin Stebner ¹, Peter Härle ¹, Frieder Kees ², Werner Falk ¹ and Jürgen Schölmerich ¹

¹ University Medical Center Regensburg, Germany
² Department of Pharmacology Regensburg, Germany

^* To whom correspondence should be addressed. E-mail: rainer.straub{at}klinik.uni-regensburg.de.

Accepted 4 April 2005

Abstract

Background: In the intestinal tract, the role of sympathetic neurotransmitters was ignored in mucosal neuroimmunology.

Aim: We aimed to investigate the influence of the sympathetic microenvironment on mucosal interplay of TNF and IL-6.

Methods: Colon strips of normal and colitic BALB/c mice were superfused in vitro. Tissue was electrically stimulated to investigate the influence of endogenous norepinephrine (NE) on secretion of IL-6 with / without anti-TNF antibodies (anti-TNF) and adrenoceptor antagonists. IL-6 was secreted from macrophages.

Results: Superfusion with anti-TNF stimulated IL-6 secretion in normal but not in colitic colon (p<0.005). Parallel superfusion with a â-adrenergic antagonist abrogated this phenomenon. Anti-TNF increased release of NE from normal colonic strips (p<0.05), which demonstrates TNF-induced inhibition of preterminal NE release. In colitic mice, anti-TNF did not change NE release. In the presence of anti-TNF, exogenous and endogenous NE stimulated colonic IL-6 secretion via â- adrenoceptors in normal (p<0.001) but not in colitic mice. In the absence of anti-TNF, endogenous and exogenous NE inhibit IL-6 secretion via the â- adrenoceptor in normal but not in colitic mice (p<0.01). Colitic mice demonstrated loss of sympathetic nerve fibres.

Conclusions: Modulation of mucosal IL-6 is largely dependent on the sympathetic microenvironment and availability of local TNF in normal but not in colitic mice. Anti-TNF strategies may lead to an increase of a proinflammatory cytokine depending on the adrenergic tone. This would be relevant with normal sympathetic innervation, which is lost in colitic mice. We present a model of sympathetic regulation of colonic macrophage TNF and IL-6 secretion.

Keywords: IL-6, TNF, colitis, macrophage, sympathetic nervous system

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