Mitogen-activated protein kinase signalling and ERK1/2 bistability in asthma

Authors

  • R. Alam,

    1. Department of Medicine, Division of Allergy & Immunology, National Jewish Health, Denver, CO, USA
    2. Department of Medicine, Health Sciences Center, Division of Allergy and Immunology, University of Colorado at Denver, Denver, CO, USA
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  • M. M. Gorska

    1. Department of Medicine, Division of Allergy & Immunology, National Jewish Health, Denver, CO, USA
    2. Department of Medicine, Health Sciences Center, Division of Allergy and Immunology, University of Colorado at Denver, Denver, CO, USA
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Correspondence:
Rafeul Alam, Department of Medicine, Division of Allergy & Immunology, National Jewish Health, 1400 Jackson Street, Denver, CO 80206, USA.
E-mail: alamr@njhealth.org

Abstract

Cite this as: R. Alam and M. M. Gorska,Clinical & Experimental Allergy, 2011 (41) 149–159.

Summary

Mitogen-activated protein kinases (MAPKs) integrate signals from numerous receptors and translate these signals into cell functions. MAPKs are critical for immune cell metabolism, migration, production of pro-inflammatory mediators, survival and differentiation. We provide a concise review of the involvement of MAPK in important cells of the immune system. Certain cell functions, e.g. production of pro-inflammatory mediators resolve quickly and may require a transient MAPK activation, other processes such as cell differentiation and long-term survival may require persistent MAPK signal. The persistent MAPK signal is frequently a consequence of positive feedback loops or double negative feedback loops which perpetuate the signal after removal of an external cell stimulus. This self-perpetuated activation of a signalling circuit is a manifestation of its bistability. Bistable systems can exist in ‘on’ and ‘off’ states and both states are stable. We have demonstrated the existence of self-perpetuated activation mechanism for ERK1/2 in bronchial epithelial cells. This sustained activation of ERK1/2 supports long-term survival of these cells and primes them for cytokine transcription. ERK1/2 bistability arises from repetitive stimulation of the cell. The repeated stimulation (e.g. repeated viral infection or repeated allergen exposure) seems to be a common theme in asthma and other chronic illnesses. We thus hypothesize that the self-perpetuated ERK1/2 signal plays an important role in the pathogenesis of asthma.

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