Mitogen-activated protein kinase signalling and ERK1/2 bistability in asthma.
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.
Department of Medicine, Division of Allergy & Immunology, National Jewish Health, Denver, CO 80206, USA. alamr@njhealth.org
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D000818:Animals; D001249:Asthma / Q000201:enzymology* / Q000378:metabolism; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015398:Signal Transduction
C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases