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Clinical & Experimental Allergy

CXCL1 is a negative regulator of mast cell chemotaxis to airway smooth muscle cell products in vitro

Authors

  • H. Alkhouri,

    Corresponding author
    1. Respiratory Research Group, Faculty of Pharmacy, The University of Sydney, Glebe; New South Wales, Australia
    • Correspondence:

      Hatem Alkhouri, Faculty of Pharmacy A15, University of Sydney, Glebe, NSW, 2006 Australia.

      E-mail: hatem.alkhouri@sydney.edu.au

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  • L. M. Moir,

    1. Respiratory Research Group, Discipline of Pharmacology, The University of Sydney, Glebe; New South Wales, Australia
    2. Woolcock Institute of Medical Research, Glebe; New South Wales, Australia
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  • C. L. Armour,

    1. Respiratory Research Group, Faculty of Pharmacy, The University of Sydney, Glebe; New South Wales, Australia
    Current affiliation:
    1. Current address: Discipline of Pharmacology, The University of Sydney and Woolcock Institute of Medical Research, Glebe; New South Wales, Australia
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  • J. M. Hughes

    1. Respiratory Research Group, Faculty of Pharmacy, The University of Sydney, Glebe; New South Wales, Australia
    2. Woolcock Institute of Medical Research, Glebe; New South Wales, Australia
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Summary

Background

Activated mast cells (MC) numbers on airway smooth muscle (ASM) are increased in eosinophilic asthma. In vitro, asthmatic cytokine-stimulated ASM cell-conditioned medium (CM) induces more MC chemotaxis than CM from nonasthmatic ASM cells. Intriguingly the nonasthmatic ASM CM inhibits MC chemotaxis to the asthmatic ASM CM. However, the inhibitory factor(s) in the nonasthmatic ASM CM is still to be identified.

Objective

To identify the factor(s) released by nonasthmatic ASM cells that inhibits MC chemotaxis.

Methods

Confluent, serum-starved ASM cells from donors with and without asthma were stimulated with IL-1β and T-helper (Th)1 (TNFα and IFNγ) or Th2 (IL-4, IL-13) cytokines, or left unstimulated. CM samples were collected after 24 h, and a potential inhibitory factor identified using cytokine protein arrays. Its production was assessed using ELISA and RT-PCR and inhibitory role investigated in MC chemotaxis and Ca2+ mobilization assays.

Results

Only CXCL1 was produced in greater amounts by nonasthmatic than asthmatic ASM cells following Th1 and Th2 cytokine stimulation. CXCL1 mRNA expression was also increased. Exogenous rh-CXCL1 significantly inhibited MC intracellular Ca2+ mobilization and chemotaxis to either CXCL10, CXCL8 or CM collected from asthmatic ASM cells following Th1 or Th2 cytokine stimulation. Neutralizing CXCL1 in nonasthmatic ASM CM or blocking its receptor significantly promoted MC chemotaxis.

Conclusions

CXCL1 was a major factor regulating MC chemotaxis in vitro. Its differential release by ASM cells may explain the differences observed in MC localization to the ASM of people with and without asthma.

Clinical Relevance

CXCL1 inhibition of MC recruitment to the ASM may lead to new targets to limit asthma pathophysiology.

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