Journal
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
Volume 302, Issue 10, Pages L1118-L1127Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00232.2011
Keywords
IFN-inducible protein 10; mRNA levels and stability; NK-kappa B; p38; ERK
Categories
Funding
- NHMRC of Australia [302073, 457457]
- Clive Foundation of Australia
- Vera Ramaciotti Foundation of Australia
- Asthma Foundation of NSW
- CRC for Asthma and Airways
- University of Sydney
- NHMRC [402835]
- UK DoH
- Wellcome Senior Fellowship
Ask authors/readers for more resources
Alrashdan YA, Alkhouri H, Chen E, Lalor DJ, Poniris M, Henness S, Brightling CE, Burgess JK, Armour CL, Ammit AJ, Hughes JM. Asthmatic airway smooth muscle CXCL10 production: mitogen-activated protein kinase JNK involvement. Am J Physiol Lung Cell Mol Physiol 302: L1118-L1127, 2012. First published March 2, 2012; doi:10.1152/ajplung.00232.2011.-CXCL10 (IP10) is involved in mast cell migration to airway smooth muscle (ASM) bundles in asthma. We aimed to investigate the role of cytokine-induced MAPK activation in CXCL10 production by ASM cells from people with and without asthma. Confluent growth-arrested ASM cells were treated with inhibitors of the MAPKs ERK, p38, and JNK and transcription factor NF-kappa B, or vehicle, and stimulated with IL-1 beta, TNF-alpha, or IFN-gamma, alone or combined (cytomix). CXCL10 mRNA and protein, JNK, NF-kappa B p65 phosphorylation, and I kappa-B alpha protein degradation were assessed using real-time PCR, ELISA, and immunoblotting, respectively. Cytomix, IL-1 beta, and TNF-alpha induced CXCL10 mRNA expression more rapidly in asthmatic than nonasthmatic ASM cells. IL-1 beta and/or TNF-alpha combined with IFN-gamma synergistically increased asthmatic ASM cell CXCL10 release. Inhibitor effects were similar in asthmatic and nonasthmatic cells, but cytomix-induced release was least affected, with only JNK and NF-kappa B inhibitors halving it. Notably, JNK phosphorylation was markedly less in asthmatic compared with nonasthmatic cells. However, in both, the JNK inhibitor SP600125 reduced JNK phosphorylation and CXCL10 mRNA levels but did not affect CXCL10 mRNA stability or I kappa-B alpha degradation. Together, the JNK and NF-kappa B inhibitors completely inhibited their CXCL10 release. We concluded that, in asthmatic compared with nonasthmatic ASM cells, JNK activation was reduced and CXCL10 gene expression was more rapid following cytomix stimulation. However, in both, JNK activation did not regulate early events leading to NF-kappa B activation. Thus JNK and NF-kappa B provide independent therapeutic targets for limiting CXCL10 production and mast cell migration to the ASM in asthma.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available