Regulation of innate immunity by suppressor of cytokine signaling (SOCS) proteins.

Innate immunity represents the first line of defense against invading pathogens. Toll-like receptors (TLRs) are important for activation of innate immunity. Moreover, cytokines mediate communication of cells and are necessary to mount an appropriately regulated immune response. However, activation of innate immunity has to be tightly controlled to avoid overshooting immune reactions. Suppressor of cytokine signaling (SOCS) proteins have been identified as inducible feedback inhibitors of cytokine receptors and have been shown to be of crucial importance for the limitation of inflammatory responses. In this review, we describe the role of SOCS proteins in macrophages and dendritic cells (DCs). Based on our own findings, we show that SOCS proteins are directly induced by stimulation of TLRs. However, SOCS proteins do not interfere with direct TLR signaling, but avoid overshooting activation by regulating paracrine IFN-beta signaling. In addition, SOCS proteins in macrophages and DCs regulate the sensitivity towards IFN-gamma and GM-CSF, thereby modulating anti-microbial activity of macrophages and differentiation of DCs. We discuss that SOCS induction can also be used by microbes to evade immune defense, and this is exemplified by the parasite Toxoplasma gondii which induces SOCS1 to inhibit IFN-gamma-mediated macrophage activation. Taken together, the findings indicate that SOCS proteins play an important role in the balanced activation of innate immunity during infectious encounter.