Two adaptor proteins prevent cells from overreacting to bacterial lipopolysaccaride (LPS), report Shinohara et al. on page 333. Dok-1 and Dok-2 dampen intracellular signals from the LPS receptor, Toll-like receptor 4 (TLR4), which may help explain how cells mount a potent response to invading bacteria without also triggering destructive inflammatory responses.

Dok-1 and Dok-2 are adaptor proteins found in hematopoietic cells that are activated by tyrosine kinases in response to antigen and cytokine receptor signals. Once activated, they suppress intracellular signals by inhibiting the GTPase Ras, thereby keeping cellular activation and multiplication under control. The importance of this control is evident in mice lacking both proteins, which have been shown to develop leukemia.

Shinohara et al. now provide evidence that these proteins also inhibit LPS-induced TLR4 signals. Dok-1 and Dok-2 are tyrosine phosphorylated within 1 minute of LPS treatment, and cells lacking either protein displayed enhanced Erk activation in response to LPS. Mice lacking these proteins died from an unchecked production of the inflammatory cytokine TNF, a cause of endotoxic shock, when given a normally sublethal dose of LPS.

This is the first standby pathway described for TLR4 inhibition in macrophages; all other macrophage TLR4 regulators are inducible, suggesting that Dok-1 and Dok-2 may be primarily responsible for controlling the rapid process of primary endotoxic shock in these cells.