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1 University of Pennsylvania School of Medicine, Philadelphia, United States
2 Pulmonary Medicine, Children's Hospital of Philadelphia, Philadelphia, United States
3 Pulmonary Medicine, Children's Hospital of Philadelphia, Philadelphia, United States; University of Pennsylvania School of Medicine, Philadelphia, United States
* To whom correspondence should be addressed. E-mail: grunstein{at}email.chop.edu.
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. Since ASM is known to directly respond to various pro-asthmatic stimuli, the potential role of TLR signaling in ASM in regulating airway expression of the pro-asthmatic 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 pro-asthmatic-like changes in the constrictor and relaxation responsiveness of isolated rabbit ASM tissues. Complimentary 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 pro-asthmatic 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 pro-asthmatic-like changes in ASM function, whereas co-activation of p38 MAPK serves to homeostatically downregulate the pro-asthmatic effects of ERK1/2 activation.
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