Toll-like receptors (TLRs) recognize pathogen-associated products, such as components of the bacterial cell wall, and activate macrophages and other innate immune cells through a signaling cascade involving serine/threonine kinases of the IRAK family. Richard Flavell and co-workers from Yale University School of Medicine, New Haven, Connecticut report in 26 July Cell that at least one member of the IRAK family, IRAK-M, is a negative regulator of TLR signaling (Cell 2002, 110:191-202). They suggest IRAK-M controls a balance between the innate immune response and excessive production of cytokines, which can be potentially harmful to the host.

Kobayashi et al. show that lack of IRAK-M causes increased production of inflammatory cytokines, including interleukin-6 and tumor-necrosis factor α, and an enhanced inflammatory response in the gut of IRAK-M^-/- mice infected with the Gram-negative pathogen Salmonella typhimurium. IRAK-M^-/- macrophages did not develop endotoxin tolerance to the bacterial lipopolysaccharide, a little-understood regulatory mechanism that protects from endotoxic shock. TLR signaling following stimulation of macrophages was enhanced in the absence of IRAK-M, and immunoprecipitations suggested that, in wild-type mice, IRAK-M inhibits the release of activating IRAK kinases from the TLR signaling complex, thereby blocking downstream signaling events.

Kobayashi et al. conclude that the negative regulatory function of IRAK-M may be required for preventing endotoxic shock and immunopathologies such as Crohn's and other inflammatory bowel diseases.