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PMID: 16341266 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid-resistant asthma patients.

The Journal of clinical investigation ·Vol. 116 ·No. 1 ·2006-01-00 ·Pages 146-55

Xystrakis E, Kusumakar S, Boswell S, Peek E, Urry Z, Richards DF, Adikibi T, Pridgeon C, Dallman M, Loke TK, Robinson DS, Barrat FJ, O'Garra A, Lavender P, Lee TH, Corrigan C, Hawrylowicz CM

Abstract

We previously reported that human CD4+ Tregs secrete high levels of IL-10 when stimulated in the presence of dexamethasone and calcitriol (vitamin D3). We now show that following stimulation by allergen, IL-10-secreting Tregs inhibit cytokine secretion by allergen-specific Th2 cells in an IL-10-dependent manner. A proportion of patients with severe asthma fail to demonstrate clinical improvement upon glucocorticoid therapy, and their asthma is characterized as glucocorticoid resistant (SR, abbreviation derived from "steroid resistant"). Dexamethasone does not enhance secretion of IL-10 by their CD4+ T cells. Addition of vitamin D3 with dexamethasone to cultures of SR CD4+ T cells enhanced IL-10 synthesis to levels observed in cells from glucocorticoid-sensitive patients cultured with dexamethasone alone. Furthermore, pretreatment with IL-10 fully restored IL-10 synthesis in these cells in response to dexamethasone. Vitamin D3 significantly overcame the inhibition of glucocorticoid-receptor expression by dexamethasone while IL-10 upregulated glucocorticoid-receptor expression by CD4+ T cells, suggesting potential mechanisms whereby these treatments may overcome poor glucocorticoid responsiveness. We show here that administration of vitamin D3 to healthy individuals and SR asthmatic patients enhanced subsequent responsiveness to dexamethasone for induction of IL-10. This strongly suggests that vitamin D3 could potentially increase the therapeutic response to glucocorticoids in SR patients.

MeSH Terms
Anti-Inflammatory Agents/therapeutic use Asthma/drug therapy,immunology CD4-Positive T-Lymphocytes/immunology Cholecalciferol/therapeutic use Dexamethasone/therapeutic use Drug Resistance/immunology Glucocorticoids/therapeutic use Humans Interleukin-10/metabolism Reference Values
Chemicals
Anti-Inflammatory Agents Glucocorticoids Interleukin-10 Cholecalciferol Dexamethasone
Authors & Affiliations
17 authors, click to expand affiliations / ORCID
Xystrakis Emmanuel
Medical Research Council and Asthma-UK Centre in Allergic Mechanisms of Asthma at King's College London, Strand, London, United Kingdom.
Kusumakar Siddharth
Boswell Sandra
Peek Emma
Urry Zoë
Richards David F
Adikibi Tonye
Pridgeon Carol
Dallman Margaret
Loke Tuck-Kay
Robinson Douglas S
Barrat Franck J
O'Garra Anne
Lavender Paul
Lee Tak H
Corrigan Christopher
Hawrylowicz Catherine M
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI21759
Published
2006-01-00
Epub
2005-00-08
Pages
146-55
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC1307558
Subset
IM
Grants
Medical Research Council · MC_U117565642 · United Kingdom
External Links
PubMed source DOI: 10.1172/JCI21759 PMC Full Text View journal details
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