Temporal regulation of cytokine mRNA expression by tristetraprolin: dynamic control by p38 MAPK and MKP-1.
Cytokines drive many inflammatory diseases, including asthma. Understanding the molecular mechanisms responsible for cytokine secretion will allow us to develop novel strategies to repress inflammation in the future. Harnessing the power of endogenous anti-inflammatory proteins is one such strategy. In this study, we investigate the p38 MAPK-mediated regulatory interaction of two anti-inflammatory proteins, mitogen-activated protein kinase phosphatase 1 (MKP-1) and tristetraprolin (TTP), in the context of asthmatic inflammation. Using primary cultures of airway smooth muscle cells in vitro, we explored the temporal regulation of IL-6 cytokine mRNA expression upon stimulation with TNF-α. Intriguingly, the temporal profile of mRNA expression was biphasic. This was not due to COX-2-derived prostanoid upregulation, increased expression of NLRP3 inflammasome components, or upregulation of the cognate receptor for TNF-α-TNFR1. Rather, the biphasic nature of TNF-α-induced IL-6 mRNA expression was regulated temporally by the RNA-destabilizing molecule, TTP. Importantly, TTP function is controlled by p38 MAPK, and our study reveals that its expression in airway smooth muscle cells is p38 MAPK-dependent and its anti-inflammatory activity is also controlled by p38 MAPK-mediated phosphorylation. MKP-1 is a MAPK deactivator; thus, by controlling p38 MAPK phosphorylation status in a temporally distinct manner, MKP-1 ensures that TTP is expressed and made functional at precisely the correct time to repress cytokine expression. Together, p38 MAPK, MKP-1, and TTP may form a regulatory network that exerts significant control on cytokine secretion in proasthmatic inflammation through precise temporal signaling.
Faculty of Pharmacy, University of Sydney, New South Wales, Australia;
Pavan
P
Prabhala
Faculty of Pharmacy, University of Sydney, New South Wales, Australia;
Kristin
K
Bunge
Faculty of Pharmacy, University of Sydney, New South Wales, Australia;
Md Mostafizur
MM
Rahman
Woolcock Institute of Medical Research, University of Sydney, New South Wales, Australia; and.
Qi
Q
Ge
Centre for Translational Inflammation Research, School of Immunity and Infection, University of Birmingham, Edgbaston, United Kingdom.
Andrew R
AR
Clark
Faculty of Pharmacy, University of Sydney, New South Wales, Australia; alaina.ammit@sydney.edu.au.
Alaina J
AJ
Ammit
D001249:Asthma / Q000276:immunology; D002352:Carrier Proteins / Q000096:biosynthesis; D002478:Cells, Cultured; D054638:Dual Specificity Phosphatase 1 / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000276:immunology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010766:Phosphorylation; D011453:Prostaglandins / Q000096:biosynthesis; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis*; D034741:RNA, Small Interfering; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000096:biosynthesis; D051816:Tristetraprolin / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D002352:Carrier Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D011453:Prostaglandins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D047888:Receptors, Tumor Necrosis Factor, Type I; D051816:Tristetraprolin; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1
IL-6; MKP-1; inflammation; p38 MAPK; tristetraprolin