Blockade of interleukin 6 trans signaling suppresses T-cell resistance against apoptosis in chronic intestinal inflammation: Evidence in Crohn disease and experimental colitis in vivo

The pro-inflammatory cytokine interleukin (IL)-6 (refs. 1-5) can bind to ce lls lacking the IL-6 receptor (IL-6R) when it forms a complex with the solu ble IL-6R (sIL-6R) (trans signaling)(5-7). Here, we have assessed the contr ibution of this system to the increased resistance of mucosal T cells again st apoptosis in Crohn disease (CD), a chronic inflammatory disease of the g astrointestinal tract(8-12). A neutralizing antibody against IL-6R suppress ed established experimental colitis in various animal models of CD mediated by type 1 T-helper cells, by inducing apoptosis of lamina propria T cells. Similarly, specific neutralization of sIL-6R in vivo by a newly designed g p130-Fc fusion protein caused suppression of colitis activity and induction of apoptosis, indicating that sIL-6R prevents mucosal T-cell apoptosis. In patients with Co, mucosal T cells showed strong evidence for IL-6 trans si gnaling, with activation of signal transducer and activator of transcriptio n 3, bcl-2 and bcl-xl. Blockade of IL-6 trans signaling caused T-cell apopt osis, indicating that the IL-6-sIL-6R system mediates the resistance of T c ells to apoptosis in CD. These data indicate that a pathway of T-cell activ ation driven by IL-6-sIL-6R contributes to the perpetuation of chronic inte stinal inflammation. Specific targeting of this pathway may be a promising new approach for the treatment of CD.