A novel negative regulator for IL-1 receptor and Toll-like receptor 4

The Toll-IL-1 receptor (TIR) superfamily, defined by the presence of an intracellular TIR domain, initiates innate immunity via NF-KB activation, leading to production of proinflammatory cytokines. ST2 is a member of the TIR family that does not activate NT-KB and has been suggested as an important effector molecule of type 2 T helper cell responses. We have recently demonstrated that the membrane bound form of ST2 (ST2L) negatively regulated IL- 1RI and TLR4 but not TLR3 signaling by sequestrating the adaptors Myd88 and Mal. In contrast to wild-type mice, ST2 deficient mice failed to develop endotoxin tolerance. Thus, ST2 suppresses IL- 1R and TLR4 signaling via MyD88 and Mal-dependent pathways and modulates innate immunity. The results provide a molecular explanation for the role of ST2 in T(H)2 responses since inhibition of TLRs will promote a T(H)2 response and also identify ST2 as a key regulator of endotoxin tolerance. (C) 2004 Elsevier B.V. All rights reserved.