MAPKs are crucial for TNF-α and IL-6 production by innate immune cells in response to TLR ligands. MAPK phosphatase (Mkp)-1 deactivates p38 and JNK MAPKs, abrogating the inflammatory response. We have previously demonstrated that Mkp-1-/- mice exhibit exacerbated inflammatory cytokine production and increased mortality in response to challenge with LPS and heat-killed Staphylococcus aureus. However, the function of Mkp-1 in host defense during live Gram-negative bacterial infection remains unclear. We infected Mkp-1+/+ and Mkp-1-/- mice with live E. coli i.v., and examined the effects of Mkp-1 deficiency on animal survival, bacterial clearance, metabolic activity and cytokine production. We found that Mkp-1 deficiency predisposed animals to accelerated mortality and was associated with more robust production of TNF-α, IL-6 and IL-10, greater bacterial burden, altered inflammatory mediator activities, and substantial changes in the mobilization of energy stores. Treatment with the bactericidal antibiotic gentamicin, given 3 h post E. coli infection, protected Mkp-1+/+ mice from septic shock yet had no effect on Mkp-1-/- mice. Thus, during Gram-negative bacterial sepsis Mkp-1 not only plays a critical role in the regulation of cytokine production but also acts to orchestrate the bactericidal activities of the innate immune system and control the metabolic response to stress.

The Research was supported by grants from NIAID (AI57798 and AI68956).