Regulation of Toll-like receptor 4-induced proasthmatic changes in airway smooth muscle function by opposing actions of ERK1/2 and p38 MAPK signaling

• Published in: American journal of physiology. Lung cellular and molecular physiology 2006-09, Vol.291 (3), p.L324-L333
• Main Authors: Shan, Xiaoyin, Hu, Aihua, Veler, Haviva, Fatma, Sumbul, Grunstein, Judith S, Chuang, Sing, Grunstein, Michael M
• Format: Article
• Language: English
• Subjects: Animals; Asthma - metabolism; Bronchi - cytology; Bronchi - metabolism; Cells, Cultured; Dose-Response Relationship, Drug; Gene Expression Regulation; Humans; In Vitro Techniques; Interleukin-6 - metabolism; Lipopolysaccharides - pharmacology; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 3 - physiology; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - physiology; NF-kappa B - metabolism; p38 Mitogen-Activated Protein Kinases - physiology; Rabbits; Time Factors; Toll-Like Receptor 4 - immunology; Toll-Like Receptor 4 - metabolism; Toll-Like Receptor 9 - metabolism; Toll-Like Receptors - metabolism
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00056.2006

The Joseph Stokes Jr. Research Institute, Division of Pulmonary Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Submitted 16 February 2006 ; accepted in final form 10 March 2006 Activation of Toll-like receptors (TLRs) on immune surveillance cells in the lung has been implicated in the pathobiology of allergic asthma, a condition associated with altered airway smooth muscle (ASM) contractility. Because ASM is known to directly respond to various proasthmatic stimuli, the potential role of TLR signaling in ASM in regulating airway expression of the proasthmatic phenotype was investigated. Cultured human ASM cells were found to express TLR4 and TLR9 mRNA transcripts and, whereas TLR9 stimulation had little effect, TLR4 activation with LPS elicited significant increases in IL-6 release and evoked proasthmatic-like changes in the constrictor and relaxation responsiveness of isolated rabbit ASM tissues. Complementary studies further demonstrated that the ASM responses to LPS were associated with activation of the ERK1/2 and p38 MAPK signaling pathways, IKK-mediated activation of NF- B, and coupling of phosphorylated ERK1/2 with the p65 subunit of NF- B. Moreover, the induced NF- B activity and changes in ASM responsiveness were prevented in LPS-exposed ASM that were pretreated with inhibitors of ERK1/2 signaling, whereas inhibition of p38 MAPK augmented the proasthmatic responses to LPS. Finally, activation of p38 MAPK with anisomycin prevented both the LPS-induced stimulation of ERK1/2-mediated NF- B activity and associated changes in ASM responsiveness. Collectively, these data support the novel concept that TLR4 activation in ASM elicits changes in ASM function that are regulated by opposing effects of MAPK signaling, wherein LPS-induced ERK1/2 activation mediates NF- B-dependent proasthmatic-like changes in ASM function, whereas coactivation of p38 MAPK serves to homeostatically downregulate the proasthmatic effects of ERK1/2 activation. asthma; lipopolysaccharide; signal transduction; mitogen-activated protein kinases; nuclear factor- B activation; cytokines; airway hyperresponsiveness Address for reprint requests and other correspondence: M. M. Grunstein, Division of Pulmonary Medicine, Abramson Research Bldg., Children's Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA 19104 (e-mail: grunstein{at}email.chop.edu )