p38 Pathway Kinases as Anti-inflammatory Drug Targets

Abstract

Mitogen-activated protein kinases (MAPK) are intracellular signaling molecules involved in cytokine synthesis. Several classes of mammalian MAPK have been identified, including extracellular signal-regulated kinase, c-jun N-terminal kinase, and p38 MAP kinase. p38alpha is a key MAPK involved in tumor necrosis factor alpha and other cytokine production, as well as enzyme induction (cyclooxygenase-2, inducible nitric oxide synthase, and matrix metalloproteinases) and adhesion molecule expression. An understanding of the broad biologic and pathophysiological roles of p38 MAPK family members has grown significantly over the past decade, as has the complexity of the signaling network leading to their activation. Downstream substrates of MAPK include other kinases (e.g., mitogen-activated protein-kinase-activated protein kinase 2) and factors that regulate transcription, nuclear export, and mRNA stability and translation. The high-resolution crystal structure of p38alpha has led to the design of selective inhibitors that have good pharmacological activity. Despite the strong rationale for MAPK inhibitors in human disease, direct proof of concept in the clinic has yet to be demonstrated, with most compounds demonstrating dose-limiting adverse effects. The role of MAPK in inflammation makes them attractive targets for new therapies, and efforts are continuing to identify newer, more selective inhibitors for inflammatory diseases.

Activation of human fibroblast-like synoviocytes by uric acid crystals in rheumatoid arthritis

“…46 The ERK pathway can be activated in RA synovial tissue and cultured RA-FLS, and the principal functional sequelae of the ERK pathway have been control of cell growth and proliferation. 47 Moreover, the JNK and ERK signaling pathways are involved in pro-inflammatory cytokine and chemokine production in activated FLS. 48,49 Numerous studies have demonstrated that the inhibition of the JNK and ERK pathways has profound effects on the synthesis of inflammatory cytokines and modulation of acute and chronic inflammation.…”

Mitogen activated protein kinases: a role in inflammatory bowel disease?

“…The g isoform of p38 is confined to skeletal muscle, while p38d is found predominantly in the testes, pancreas and small intestines; however, both are in contrast to the a and b forms, which are expressed ubiquitously [12]. The p38 MAPKs are known to be activated by the MAPKKs MKK3 and MKK6.…”

“…1). Phosphorylation of this motif in the catalytic loop allows a conformational change to occur whereby the kinase active site is revealed to allow substrate binding [10,12]. Additionally, some MAPKs have peculiar features: ERK5 has a transactivation domain and along with ERK7 possesses a nuclear localization signal; NLK contains an alanine, histidine and glutamine-rich domain, and ERK3 and 4 have a conserved region specific for these kinases (Fig.…”

Toll-like receptor-mediated adjuvanticity and immunomodulation in dendritic cells: Implications for peptide vaccines

“…21 In addition, p38 MAPK inhibitors are being investigated in clinical trials as anti-inflammatory drug targets for the treatment of inflammatory and autoimmune disorders. 22 Pinpointing which MAPK pathways are important in the production of Th-promoting cytokines in the response of DCs to stimulation by different TLRs, may lead to the identification of new strategies for specifically targeting MAPKs to modulate immune responses. In addition to the MAPKs, there are additional kinases that seem to be important in regulating TLR signaling.…”