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

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.