The impact of precise MKP-1 regulation and modulation on cytokine expression in asthma and airway remodelling

Abstract

Asthma is a chronic inflammatory disease characterised by airway obstruction, hyperresponsiveness and remodelling. Cytokines drive many inflammatory diseases and change the balance of inflammatory and anti-inflammatory molecules along the underlying molecular pathways. Hence targeting the molecular mechanisms responsible for cytokine secretion allows us to develop novel strategies to repress inflammation. Harnessing the power of endogenous anti-inflammatory proteins is one such strategy. In this study we investigate the p38 MAPK-mediated anti-inflammatory molecule; mitogen-activated protein kinase phosphatase 1 (MKP-1). MKP-1 is a MAPK deactivator; thus, by controlling p38 MAPK phosphorylation status in a temporally-distinct manner, MKP-1 is able to repress cytokine expression, via the action of another anti-inflammatory molecule; tristetraprolin (TTP). The structure of MKP-1 can be manipulated at the level of transcription and translation. We specifically focused on the post-translational changes to increase its longevity and possibly its activity. This was achieved through the use of inhaled corticosteroids and by altering the proteasome-MKP-1 binding domain. Utilizing primary cultures of airway smooth muscle cells in vitro we explored the temporal regulation of IL-6 cytokine expression upon stimulation with tumor necrosis factor  (TNF). IL-6 cytokine expression was then used as a model to explore the interaction between p38 MAPK induced anti-inflammatory molecules MKP-1 and TTP. We show that cytokine expression in ASM cells is p38 MAPK-dependent and that the anti-inflammatory regulatory network is also controlled by p38 MAPK-mediated phosphorylation. We also show that the balance of this regulatory network can be altered in the presence of dexamethasone or compounds that interrupt the proteasomal binding of MKP-1. Together, p38 MAPK, MKP-1 and TTP may form a regulatory network that exerts significant control on cytokine secretion, which can then be altered.