IL-12 promotes the proliferation of T cells as well as NK cells and plays a critical role in induction of the Th1 differentiation. IL12 mediates its biological activities through activation of the receptor-associated JAK family kinases and STAT4. which is recruited to phosphorylated Tyr-800 in the human IL-12 receptor beta2 subunit (IL-12Rbeta2). Here we demonstrate that suppressor of cytokine signaling-3 (SOCS-3) is also recruited to IL-12Rbeta2 by the interaction involving the SOCS-3 SH2 domain and phosphorylated Tyr-800 in IL-12Rbeta2. Furthermore, SOCS-3, but not its SH2 domain-defective mutant, inhibited the IL-12-induced activation of DNA-binding and transcriptional activities of STAT4. These results suggest that SOCS-3, expressed at high levels in Th2 cells, plays an inhibitory role in STAT4-mediated IL-12 signaling by binding to the STAT4 docking site in IL-12Rbeta2, thus raising a possibility that SOCS-3 may play a role in regulation of Th differentiation. (C) 2003 Elsevier Inc. All rights reserved.