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Review
. 2011 Feb;41(2):149-59.
doi: 10.1111/j.1365-2222.2010.03658.x. Epub 2010 Dec 1.

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

R Alam  1 , M M Gorska
Affiliations
Review

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

R Alam et al. Clin Exp Allergy. 2011 Feb.

Abstract

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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Figures

Figure 1
Figure 1
The importance of ERK, p38 and JNK in asthma.
Figure 2
Figure 2
Top panel: A diagrammatic presentation of analog and digital output of pERK1/2 with the increasing concentration of an agonist. Bottom panel, left: A monostable system showing a linear dose-response relationship. Right: A bistable system showing a non-linear hysteretic property with the increasing concentration of the agonist.
Figure 3
Figure 3
A schematic presentation of positive and double negative feedback loops leading to ERK1/2 bistability
See this image and copyright information in PMC

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