The inflammatory response to lipopolysaccharide (LPS) is crucial for protecting the host against pathogenic bacteria, but excessive cytokine production can be harmful and, in some cases, fatal if LPS-induced shock occurs. Therefore, LPS signalling, through the LPS receptor Toll-like receptor 4 (TLR4), needs to be controlled tightly. But, how is this achieved? Two papers in Immunity now indicate a central role for suppressor of cytokine signalling 1 (SOCS1) in the negative regulation of LPS signalling.

SOCS1 was identified initially as a negative regulator of signalling downstream of cytokines. However, SOCS1 is expressed by macrophages after stimulation with LPS. This fact, combined with the observation that Socs1−/− mice develop inflammatory organ disease, led the authors to ask whether SOCS1 downmodulates LPS signalling.

Both groups looked at the effect of SOCS1 deficiency on the response to LPS. Nakagawa et al. showed that Socs1−/− mice (pre-disease onset) and Socs1+/− mice are hyper-responsive to LPS and are sensitive to LPS-induced lethality. Macrophages from these mice produced increased amounts of the pro-inflammatory cytokines tumour-necrosis factor (TNF) and interleukin-12 (IL-12). Kinjyo et al. also investigated the response of Socs+/− mice to LPS. First, they crossed these mice onto an interferon-γ (IFN-γ)-deficient background to eliminate any effect of SOCS1 on IFN-γ signalling. IFN-γ-deficient Socs1−/− and IFN-γ-deficient Socs1+/− mice were more sensitive than IFN-γ-deficient Socs1+/+ mice to LPS, and macrophages from these mice produced high levels of TNF and nitric oxide in response to LPS.

When wild-type mice are treated with a low dose of LPS, they are protected from the effects of a higher, potentially fatal, dose when administered later on. This phenomenon is known as 'LPS tolerance'. Is SOCS1-mediated downregulation of LPS signal transduction important for this protective mechanism? These studies showed that a similar pre-treatment of Socs1−/− mice and Socs1−/− macrophages with LPS did not protect them from a subsequent higher dose, indicating that SOCS1 is required for LPS tolerance.

To find out how SOCS1 regulates the response to LPS, both groups overexpressed SOCS1 in a macrophage cell line. SOCS1-overexpressing macrophages produced little nitric oxide and TNF in response to LPS, and the activities of signal transducer and activator of transcription 1 (STAT1) and nuclear factor-κB (which are both required for the generation of nitric oxide) were reduced in these cells.

These studies show that, in addition to a central role in controlling adaptive immune responses downstream of cytokines, SOCS1 can suppress TLR4 signalling directly and modulate the innate immune response.