Regulatory Effect of SOCS on NF-κB Activity in Murine Monocytes/Macrophages

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Abstract
The suppressor of cytokine signaling (SOCS) group of proteins has been implicated in regulation of various cytokine signaling and in a negative crosstalk between distinct signaling pathways. Interleukin-10 (IL-10) and LPS were known to induce expression of SOCS-3 in neutrophils and monocytes/macrophages. IL-10 was also reported to inhibit a proinflammatory signal-induced NF-κB activation in monocytes and peripheral T lymphocytes. The effects of increased SOCS-3 expression upon IL-10 regulation of NF-κB activation have not yet been demonstrated. Here we examined the effects of SOCS-3 on NF-κB activity. SOCS-3 did not induce any alterations in NF-κB activity induced by LPS or TNF-α. However, it enhanced RelA-dependent κB promoter activity when cotransfected with RelA. Similar results were observed with SOCS-1. In contrast, SOCS-2 did not show any regulatory effects on RelA activity. Analysis of C-terminal truncation mutants of SOCS-1 and SOCS-3 demonstrated that the SOCS box and its N-terminal region, a less well-conserved linker region were important for SOCS-3 activation of RelA. In contrast, the SOCS box itself was critical for SOCS-1 to activate RelA. These results suggest that SOCS proteins can enhance the effects of NF-κB/Rel proteins, and therefore, further modulate immune and inflammatory responses.