Extracellular signal–regulated kinase 5 promotes acute cellular and systemic inflammation

Inhibition of the mitogen-activated protein kinase ERK5 reduces systemic inflammation in mice. Inflamed by ERK5 Because of their importance in stimulating the production of proinflammatory cytokines, some members of the mitogen-activated protein kinase (MAPK) family have been targeted therapeutically to treat inflammatory diseases. However, clinical trials with such drugs have proved disappointing, spurring the search for other potential candidates. Wilhelmsen et al. found that another MAPK family member, extracellular signal–regulated kinase 5 (ERK5), promoted inflammatory responses to microbial stimuli in human endothelial and immune cells. Furthermore, inhibitors of ERK5 and its upstream activating kinase MEK5 reduced systemic inflammation in various mouse models of microbial infection and noninfectious tissue injury, raising the possibility that ERK5 might have therapeutic potential for the treatment of inflammatory disorders. Inflammatory critical illness is a syndrome that is characterized by acute inflammation and organ injury, and it is triggered by infections and noninfectious tissue injury, both of which activate innate immune receptors and pathways. Although reports suggest an anti-inflammatory role for the mitogen-activated protein kinase (MAPK) extracellular signal–regulated kinase 5 (ERK5), we previously found that ERK5 mediates proinflammatory responses in primary human cells in response to stimulation of Toll-like receptor 2 (TLR2). We inhibited the kinase activities and reduced the abundances of ERK5 and MEK5, a MAPK kinase directly upstream of ERK5, in primary human vascular endothelial cells and monocytes, and found that ERK5 promoted inflammation induced by a broad range of microbial TLR agonists and by the proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor–α (TNF-α). Furthermore, we found that inhibitors of MEK5 or ERK5 reduced the plasma concentrations of proinflammatory cytokines in mice challenged with TLR ligands or heat-killed Staphylococcus aureus, as well as in mice that underwent sterile lung ischemia-reperfusion injury. Finally, we found that inhibition of ERK5 protected endotoxemic mice from death. Together, our studies support a proinflammatory role for ERK5 in primary human endothelial cells and monocytes, and suggest that ERK5 is a potential therapeutic target in diverse disorders that cause inflammatory critical illness.