Anti-inflammatory effects of tumour necrosis factor (TNF)-α are mediated via TNF-R2 (p75) in tolerogenic transforming growth factor-β-treated antigen-presenting cells

Abstract

Exposure of macrophages to transforming growth factor (TGF)-β is known to alter their functional phenotype such that antigen presentation by these cells leads to tolerance rather than an inflammatory immune response. Typically, eye-derived antigen-presenting cells (APCs) exposed to TGF-β in the local environment are known to induce a form of peripheral tolerance and protect the eye from inflammatory immune effector-mediated damage. In response to TGF-β, APCs increase their expression of tumour necrosis factor (TNF)-α and TNF receptor 2 (TNF-R2). Although TNF-α has been implicated in tolerance and the associated regulation of the inflammatory immune response, its source and the receptors involved remain unclear. In this report we determined the contribution of TNF-α and TNF-R2 expressed by TGF-β-treated APCs to their anti-inflammatory tolerogenic effect. Our results indicate that APC-derived TNF-α is essential for the ability of APCs to regulate the immune response and their IL-12 secretion. Moreover, in the absence of TNF-R2, APCs exposed to TGF-β failed to induce tolerance or regulatory cells known to participate in this tolerance. Also, blocking of TNF-R1 signalling enhanced the ability of the APCs to secrete increased TGF-β in response to TGF-β exposure. Together our results support an anti-inflammatory role of TNF-α in regulation of an immune response by TGF-β-treated APCs and suggest that TNF-R2 contributes significantly to this role. © 2008 Blackwell Publishing Ltd.