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p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases

Key Points

  • Mitogen-activated protein kinases (MAPKs) integrate and process various extracellular signals. A series of three protein kinases — a MAPK and two upstream components, MAPK kinase (MAPKK) and MAPKK kinase (MAPKKK) — constitutes the MAPK cascade.

  • So far, three distinct MAPK pathways have been described in mammalian cells: the extracellular signal-regulated kinases (ERKs) pathway, the c-Jun amino terminal kinase (JNK) pathway and the p38 MAPK pathway. In general, the ERKs are activated by mitogenic and proliferative stimuli, whereas the JNKs and p38 MAPKs respond to environmental stress, including ultraviolet light, heat, osmotic shock and inflammatory cytokines.

  • Four homologues/isoforms of p38 MAPK have been identified: p38α, p38β, p38γ and p38δ. Of these, p38α is the best characterized and perhaps the most physiologically relevant kinase involved in inflammatory responses.

  • p38 MAPK is activated by dual phosphorylation on Thr180 and Tyr182 by an upstream MAPKK termed MAP2K6. Other MAPKKs, such as MAP2K3, have also been suggested to activate p38 MAPK. MAP2K6 is activated by several MAPKKKs, which are activated by a wide variety of stimuli. An MAPKK-independent mechanism of p38 activation involving TAB1 (transforming growth factor-β-activated protein kinase 1 (TAK1)-binding protein 1) has also been described.

  • The p38α MAPK pathway is crucial to inflammatory cytokine production and signalling. Several p38 MAPK inhibitors have been shown to block the production of interleukin (IL)-1, tumour-necrosis factor (TNF) and other cytokines. The inhibition of cytokine production seems to result from combined effects at the level of transcription and translation.

  • Several different classes of p38 MAPK inhibitor have been discovered. A large body of evidence from preclinical studies with these inhibitors indicates a crucial role of p38 MAPK in inflammation.

  • On the basis of these studies, several of the more promising compounds have entered human clinical trials for conditions such as rheumatoid arthritis.

Abstract

The p38 MAP kinases are a family of serine/threonine protein kinases that play important roles in cellular responses to external stress signals. Since their identification about 10 years ago, much has been learned of the activation and regulation of the p38 MAP kinase pathways. Inhibitors of two members of the p38 family have been shown to have anti-inflammatory effects in preclinical disease models, primarily through the inhibition of the expression of inflammatory mediators. Several promising compounds have also progressed to clinical trials. In this review, we provide an overview of the role of p38 MAP kinases in stress-activated pathways and the progress towards clinical development of p38 MAP kinase inhibitors in the treatment of inflammatory diseases.

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Figure 1: Generic MAP kinase pathways.
Figure 2: p38 MAPK pathway activators and substrates.
Figure 3: Schematic representation of inhibition of TNF/IL-1 messenger RNA translation and transcription.
Figure 4: Structures of representative classes of p38 MAP kinase inhibitors.
Figure 5: Crystallographic data for p38 MAPK.
Figure 6: Structures of p38 MAP kinase inhibitors that have advanced to clinical trials.

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Acknowledgements

The authors wish to acknowledge N. Nevins for her contribution to the illustration in Fig. 5 and S. Blake for critical reading of the manuscript.

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DATABASES

LocusLink

DUSP10

DUSP16

ERK1

ERK2

JNK1

MAP2K3

MAP2K6

p38α MAPK

p38δ

p38γ

TAB1

Online Mendelian Inheritance in Man

Alzheimer's disease

Crohn's disease

inflammatory bowel disease

rheumatoid arthritis

FURTHER INFORMATION

Encyclopedia of Life Sciences

cytokines

Glossary

3′ UNTRANSLATED REGION

Part of the sequence in a messenger RNA molecule at the 3′ end of the coding sequence that is not translated. This structural feature is involved in mRNA stability or turnover.

PHARMACOPHORE

The ensemble of steric and electronic features that is necessary to ensure optimal interactions with a specific biological target structure and to trigger (or to block) its biological response.

CRYPTIC PROMOTERS

Promoter regions that do not contain recognized sequence elements corresponding to a classical promoter sequence.

ACR20

A 20% response rate according to American College of Rheumatology clinical classification criteria.

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Kumar, S., Boehm, J. & Lee, J. p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov 2, 717–726 (2003). https://doi.org/10.1038/nrd1177

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