TNF suppresses acute intestinal in!ammation by inducing local glucocorticoid synthesis

TNF is a well-characterized proin!ammatory cytokine with a critical role in the pathogenesis of various in!ammatory diseases (Eigler et al., 1997). The importance of TNF in the initiation of in!ammatory disorders is particularly obvious in in!ammatory bowel disease (IBD), such as Crohn’s disease and ulcerative colitis, where unrestrained reactions against luminal antigens and commensal bacteria result in devastating in!ammatory responses in the intestinal mucosa. TNF is rapidly induced in the intestinal mucosa upon initial activation of immune cells and seems to be important for the further acceleration of the in!ammatory response. Consequently, absence or inhibition of TNF activity ameliorates disease progression in different experimental IBD models and human patients (Neurath et al., 1997; Corazza et al., 1999; Papadakis and Targan, 2000). Apart from its well-characterized proin!ammatory role, there is increasing evidence for various antiin!ammatory properties of TNF. For example, although TNF is critical for the initiation of experimental autoimmune encephalomyelitis, it is also involved in the resolution of the disease (Kassiotis and Kollias, 2001). Similar observations have been made in dextran sodium sulfate (DSS)–induced colitis, where the absence or neutralization of TNF leads to an exacerbation of disease (Naito et al., 2003). These antiin!ammatory properties of TNF may be attributed at least in part to its apoptosis-modulating activities in immune cells (Zheng et al., 1995). In particular, TNF strongly sensitizes T cells to apoptosis induction, resulting in an accelerated resolution of the in!ammatory response (Zhou et al., 1996). Although the antiin!ammatory e"ects of TNF on activated T cells are well described, little is known about its immunosuppressive activity in nonimmune cells. Glucocorticoids (GCs) are steroid hormones with potent antiin!ammatory properties (Riccardi et al., 2002). Thus, a variety of inflammatory disorders are successfully treated with GCs. Endogenous GCs are predominantly produced in the adrenal glands in response to emotional, physical, and immunological stress. Consequently, removal of the adrenal glands or pharmacological inhibition of systemic GC synthesis may result in shock or death after induction of a strong immune response (Gonzalo et al., 1993). Over the last decade, there has CORRESPONDENCE Thomas Brunner: [email protected]