The Role of Mnk-1, Eukaryotic Translation Initiation Factors and Translation Control in the Pathogenesis of Asthma

Asthma is the most common chronic inflammatory disease of the lung and is characterised by inflammation and airway wall remodelling. Chronic inflammation can be controlled by inhaled antiinflammatory drugs, while airway wall remodelling can only be limited by bronchial thermoplasty. The mechanism that leads to airway wall remodelling is not well understood and recent studies suggested that epigenetics play a major role in asthma pathogenesis. Epigenetics describe mechanisms that modify the expression of genes without changing the genetic code. Epigenetic events can be triggered by environmental factors and even be inherited over several generations. In asthma, there is evidence suggesting that epigenetic events lead to faulty translation control of specific proteins. Mitogen activated protein kinase interacting serine/threonine-protein kinase 1 (Mnk-1) and eukaryotic translation initiation factor (eIF4E) are two major controllers for the initiation of mRNA translation into proteins. Mnk-1 controls mRNA stability, its export from the nucleus and the initiation of translation through eIF4E. In asthma, the expression of several proinflammatory cytokines and factors that contribute to remodelling have been linked to deregulated action of the translation initiating protein eIF4E or its ligand eIF4E binding protein. The expression and action of eIF4E is regulated by Mnk-1 and mTOR, both have been recently associated with asthma pathologies. The best studied proteins that are regulated via translation control in asthma are: Nox4, C/EBPα, p38, calveolin-1, CXCL10 and eotaxin. The aim of this review is to establish a hypothesis where deregulated translation control is driving the pathogenesis of asthma.