Editors' ChoiceImmunology

SOCS, A Master Attenuator

Science's STKE  26 Nov 2002:
Vol. 2002, Issue 160, pp. tw437-TW437
DOI: 10.1126/stke.2002.160.tw437

Suppressor of cytokine signaling (SOCS) proteins attenuate signaling pathways by providing a negative feedback signal to prevent excessive cellular activation that can be lethal. Although best known for their role in limiting signaling through the Janus kinase (Jak)-signal transducer and activator of transcription (STAT) pathway, these proteins are also being implicated as negative regulators of noncytokine pathways (see Related Resources). Kinjyo et al. and Nagakawa et al. both investigated the responsiveness of SOCS1-/- mice and macrophages to the bacterial product lipopolysaccharide (LPS), which stimulates the Toll-like receptor TLR4. Analysis in the proper genetic background allowed the researchers to isolate the SOCS effect from its effect on cytokine signaling. Both groups reported increased mortality in response to LPS compared with wild-type mice and enhanced macrophage signaling measured as production of nitrite and tumor necrosis factor-α (TNF-α). Kinjyo et al. reported increased phosphorylation of the inhibitor of κB (IκB), the stress response kinase p38, and c-Jun NH2-terminal kinase (JNK) in SOCS-deficient macrophages after LPS treatment. Both groups also reported impaired induction of tolerance to LPS--that is the SOCS-deficient macrophages and mice, unlike wild type, did now show a decreased responsiveness or mortality to a second exposure to LPS. Finally, both groups found that overexpression of SOCS1 inhibited activation of the transcription factor NF-κB. Thus, SOCS are not just for cytokines anymore.

I. Kinjyo, T. Hanada, K. Inagaki-Ohara, H. Mori, D. Aki, M. Ohishi, H. Yoshida, M. Kubo, A. Yoshimura, SOCS1/JAB is a negative regulator of LPS-induced macrophage activation. Immunity 17, 583-591 (2002). [Online Journal]

R. Nakagawa, T. Naka, H. Tsutsui, M. Fujimoto, A. Kimura, T. Abe, E. Seki, S. Sato, O. Takeuchi, K. Takeda, S. Akira, K. Yamanishi, I. Kawase, K. Nakanishi, T. Kishimoto, SOCS-1 participates in negative regulation of LPS responses. Immunity 17, 677-687 (2002). [Online Journal]