Dubai Final-v20.indd - World Allergy Organization

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EPiTHElial CEll DEriVED CHEmoKinES EnHanCE THE ProliFEraTion anD SUrViVal oF airWaY SmooTH mUSClE CEllS
Via THE aCTiVaTion oF ErK1/2 Signaling PaTHWaY
Al-muhsen, s. 1 , Halwani, r. 2 , Al-Jahdali, H. 3 and Hamid, Q. 4
1 2 Department of Pediatrics, College of medicine, King saud University. Asthma research Chair and Prince naif Center for
immunological research, College of medicine, King saud University., riyadh, saudi Arabia. 3King saud University for health sciences,
riyadh, saudi Arabia. 4mcgill University, meakins-Christie laboratories, montreal, Canada.
Background: the increase in AsmC mass is a major structural change described in asthma. this increase has been attributed to
AsmC hyperplasia and hypertrophy. recent studies have suggested a role of chemokines in smC migration toward the epithelium.
the objective of the current study is to test the hypothesis that chemokines (Eotaxin, rAntEs, il-8 and miP-1α) can increase the
rate of proliferation and enhance the survival of Asm cells.
methods: AsmCs were exposed to different concentrations of eotaxin, rAntEs, il-8 or miP-1α. to test for proliferation, stimulated
AsmC were pulsed with 3H-thymidine or AsmCs were stained with BrdU and then analyzed with flow cytometry. Apoptosis was
measured using Annexin-V and flow cytometry.
results: in a concentration-dependent manner, chemokines such as Eotaxin, rAntEs, il-8 and miP-1α increased AsmCs
3H-thymidine incorporation and DnA synthesis. this increase, however, was inhibited using ErK1/2 phosphorylation inhibitors. il-8,
Eotaxin, and miP-1α decreased the number of apoptotic AsmCs compared to the matched controls.
Conclusion: We conclude that chemokines might contribute to airway remodeling seen in asthma by increasing Asm mass through
enhancing AsmCs proliferation and survival.
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TH-17 CYToKinE moDUlaTion oF STEroiD inSEnSiTiViTY in PEriPHEral BlooD mononUClEar CEllS
Vazquez tello, A. 1 , Halwani, r. 2 , Al-muhsen, s. 3 and Hamid, Q. 4
1Asthma research Chair and Prince naif center for immunology research, College of medicine, King saud University, riyadh, saudi
Arabia. 2Asthma research Chair and Prince naif Center for immunological research, College of medicine, King saud University.,
riyadh, saudi Arabia. 3Department of Pediatrics, College of medicine, King saud University. 4mcgill University, meakins-Christie
laboratories, montreal, QC, Canada.
Background. inhaled corticosteroids represent the most common treatment for asthma. Although most asthmatic patients respond
well, a significant proportion of severe asthmatic patients either require high doses or even fail to respond to oral or inhaled
corticosteroids. We have previously reported that glucocorticoid receptor-beta is associated with corticosteroid resistance. We
have also shown that in severe asthmatic patients, th-17 cytokines increase steroid insensitivity in airway epithelial cells via a
mechanism involving gr-beta upregulation.
objective. to investigate whether il-17A and F cytokines enhance steroid unresponsiveness in PBmCs isolated from normal and
severe asthmatic subjects via the upregulation of gr-beta isoform.
methods. PBmCs were isolated from the blood of healthy and severe asthmatics subjects and cultured for 48 hours in the presence
or absence of il-17A, il-17F, il-17A+il-17F, or il-2+il-4 cytokines. inhibition of proliferation by Dexamethasone (iC50) was then
assessed on PHA-treated cells using 3H-thymidine pulse labeling. Expression of gr-alpha, gr-beta, gilZ and il-6 was determined
using real time rt-PCr and/or Western blotting.
results. treatment of PBmCs with il-17A+F cytokines significantly decreased the level of expression of gr-alpha m-rnA while
the of expression of gr-beta m-rnA was significantly upregulated. moreover, while treating PBmCs with il-2+il-4 had a more
remarkable decrease in gr-alpha expression, this cytokine combination had no effect on gr-beta receptors. Both cytokine
combinations significantly decreased the inhibitory effect of Dexamethasone on PBmC proliferation (il-17A+F, iC50=190 nm Dex;
il-2+4, iC50=1060 nm Dex); no significant differences were observed between the PBmCs from normal subjects and severe
asthmatics. treatment with il-2+4, but not il-17A+F, inhibited the dexamethasone-induced expression of the glucocorticoidinducible
leucine zipper gene (gilZ) in PBmCs from both normal (60%) and asthmatics (45-50%).
Conclusion. il-17A, il-17F, il-2 and il-4, which are known to be upregulated in the blood and lung tissue of asthmatics, contribute
to steroid insensitivity of severe asthmatic patients by modulating the expression of gr-alpha and gr-beta receptors on peripheral
blood PBmCs. Furthermore, the increased gr-beta/gr-alpha ratios by both il-17A+F and il-2+4 cytokines correlates with the
decreased inhibitory effect of Dexamethasone on PHA-induced PBmC proliferation.
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