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

Abstract

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.

The Proteasome Inhibitor Bortezomib Inhibits Inflammatory Response of Periodontal Ligament Cells and Ameliorates Experimental Periodontitis in Rats

“…The MAPK‐mediated pathway is another vital signaling pathway involved in LPS‐induced inflammation 4 . As a new member of the MAPK family, the role of ERK5 in inflammatory response has attracted much attention 24 , 25 . In this study, it was found that ERK5 also participated in the inflammatory response in LPS‐stimulated hPDLCs besides p38, ERK1/2, and JNK.…”

ERK5 kinase activity is dispensable for cellular immune response and proliferation

“…ERK5 has been recently studied as a target for mediating inflammation (23,24,26). We determined the activity of the ERK5 compounds in cellular assays of inflammatory response.…”

“…The interpretability of removing the entire protein is typically justified when small molecule inhibitors can demonstrate the same phenotype. In multiple studies (20,(22)(23)(24)(25), ERK5 kinase inhibition using XMD8-92 has been used in parallel to siRNA-mediated knockdown of ERK5 to show two lines of supporting evidence for ERK5′s role. Given the lack of cellular effect by selective ERK5 kinase inhibitors, we used siRNA to deplete ERK5 in the HUVECs and BEAS-2B cells to evaluate the role of ERK5 presence.…”

“…We sought to analyze the effects of selective ERK5 inhibition in comparison to BRD inhibition (either dual ERK/BRD or BRD-only) on genome-wide gene expression. Two cellular models with reported ERK5-regulated signaling were used: Pam 3 CSK 4 -stimulated HUVECs (23,24) as a model of inflammation, and EGF-stimulated HeLa cells (5,20,29) as an established cell model of ERK5 regulation. Cells were preincubated with DMSO vehicle, AX15836 (ERK5 inhibitor), AX15839 (dual ERK5/BRD inhibitor), or I-BET762 (BRD inhibitor) and then stimulated with agonist.…”

“…Effects of this inhibitor on cell proliferation were shown to be comparable to overexpression of a dominant negative ERK5 mutant (20,21) or to siRNA-mediated ERK5 knockdown (21,22), implicating a key role of the kinase function. Multiple reports have shown promising and corroborating effects of ERK5 knockdown and pharmacological inhibition in controlling inflammation and tumor growth (20,(22)(23)(24)(25)(26).Given the proposed therapeutic uses for ERK5 inhibitors, we set out to develop improved compounds with high selectivity and potency. With these ERK5 compounds, we show that first-generation ERK5 inhibitors actually derived the bulk of their biological activity from off-target activity on bromodomains (BRDs).…”