IFN-gamma, IL-4 and IL-13 Modulate Responsiveness of Human Airway Smooth Muscle Cells to IL-13

Overview

Journal Respir Res

Specialty Pulmonary Medicine

Date 2009 Jan 1

PMID 19116009

Citations 18

Authors

Barry J Moynihan

Barbara Tolloczko

Souad El Bassam

Pascale Ferraro

Marie-Claire Michoud

James G Martin

Sophie Laberge

Affiliations

Soon will be listed here.

Abstract

Background: IL-13 is a critical mediator of allergic asthma and associated airway hyperresponsiveness. IL-13 acts through a receptor complex comprised of IL-13Ralpha1 and IL-4Ralpha subunits with subsequent activation of signal transducer and activator of transcription 6 (STAT6). The IL-13Ralpha2 receptor may act as a decoy receptor. In human airway smooth muscle (HASM) cells, IL-13 enhances cellular proliferation, calcium responses to agonists and induces eotaxin production. We investigated the effects of pre-treatment with IL-4, IL-13 and IFN-gamma on the responses of HASM cells to IL-13.

Methods: Cultured HASM were examined for expression of IL-13 receptor subunits using polymerase chain reaction, immunofluorescence microscopy and flow cytometry. Effects of cytokine pre-treatment on IL-13-induced cell responses were assessed by looking at STAT6 phosphorylation using Western blot, eotaxin secretion and calcium responses to histamine.

Results: IL-13Ralpha1, IL-4Ralpha and IL-13Ralpha2 subunits were expressed on HASM cells. IL-13 induced phosphorylation of STAT6 which reached a maximum by 30 minutes. Pre-treatment with IL-4, IL-13 and, to a lesser degree, IFN-gamma reduced peak STAT6 phosphorylation in response to IL-13. IL-13, but not IFN-gamma, pre-treatment abrogated IL-13-induced eotaxin secretion. Pre-treatment with IL-4 or IL-13 abrogated IL-13-induced augmentation of the calcium transient evoked by histamine. Cytokine pre-treatment did not affect expression of IL-13Ralpha1 and IL-4Ralpha but increased expression of IL-13Ralpha2. An anti-IL-13Ralpha2 neutralizing antibody did not prevent the cytokine pre-treatment effects on STAT6 phosphorylation. Cytokine pre-treatment increased SOCS-1, but not SOCS-3, mRNA expression which was not associated with significant increases in protein expression.

Conclusion: Pre-treatment with IL-4 and IL-13, but not IFN-gamma, induced desensitization of the HASM cells to IL-13 as measured by eotaxin secretion and calcium transients to histamine. The mechanism of IL-4 and IL-13 induced desensitization does not appear to involve either downregulation of receptor expression or induction of the IL-13Ralpha2 or the SOCS proteins.

Citing Articles

Leptin augments IL-13-induced airway eotaxins and submucosal eosinophilia in obesity-associated asthma.

Ingram J, McQuade V, Weiss J, Womble J, Ihrie M, Zhao K J Allergy Clin Immunol. 2024; 155(3):819-833.e10.

PMID: 39581293 PMC: 11875949. DOI: 10.1016/j.jaci.2024.10.039.

Determining the toxicological effects of indoor air pollution on both a healthy and an inflammatory-comprised model of the alveolar epithelial barrier in vitro.

Meldrum K, Evans S, Burgum M, Doak S, Clift M Part Fibre Toxicol. 2024; 21(1):25.

PMID: 38760786 PMC: 11100169. DOI: 10.1186/s12989-024-00584-8.

Epithelial-Mesenchymal Transition Mechanisms in Chronic Airway Diseases: A Common Process to Target?.

Mottais A, Riberi L, Falco A, Soccal S, Gohy S, De Rose V Int J Mol Sci. 2023; 24(15).

PMID: 37569787 PMC: 10418908. DOI: 10.3390/ijms241512412.

New insights into the pathophysiology and therapeutic targets of asthma and comorbid chronic rhinosinusitis with or without nasal polyposis.

Striz I, Golebski K, Strizova Z, Loukides S, Bakakos P, Hanania N Clin Sci (Lond). 2023; 137(9):727-753.

PMID: 37199256 PMC: 10195992. DOI: 10.1042/CS20190281.

Airway remodeling heterogeneity in asthma and its relationship to disease outcomes.

Hsieh A, Assadinia N, Hackett T Front Physiol. 2023; 14:1113100.

PMID: 36744026 PMC: 9892557. DOI: 10.3389/fphys.2023.1113100.

References

Chen Q, Rabach L, Noble P, Zheng T, Lee C, Homer R . IL-11 receptor alpha in the pathogenesis of IL-13-induced inflammation and remodeling. J Immunol. 2005; 174(4):2305-13. DOI: 10.4049/jimmunol.174.4.2305. View

Daines M, Khurana Hershey G . A novel mechanism by which interferon-gamma can regulate interleukin (IL)-13 responses. Evidence for intracellular stores of IL-13 receptor alpha -2 and their rapid mobilization by interferon-gamma. J Biol Chem. 2002; 277(12):10387-93. DOI: 10.1074/jbc.M108109200. View

Fichtner-Feigl S, Strober W, Kawakami K, Puri R, Kitani A . IL-13 signaling through the IL-13alpha2 receptor is involved in induction of TGF-beta1 production and fibrosis. Nat Med. 2005; 12(1):99-106. DOI: 10.1038/nm1332. View

Kuperman D, Huang X, Koth L, Chang G, Dolganov G, Zhu Z . Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Nat Med. 2002; 8(8):885-9. DOI: 10.1038/nm734. View

Hebenstreit D, Luft P, Schmiedlechner A, Duschl A, Horejs-Hoeck J . SOCS-1 and SOCS-3 inhibit IL-4 and IL-13 induced activation of Eotaxin-3/CCL26 gene expression in HEK293 cells. Mol Immunol. 2004; 42(3):295-303. DOI: 10.1016/j.molimm.2004.09.004. View

Shore S, Moore P . Effects of cytokines on contractile and dilator responses of airway smooth muscle. Clin Exp Pharmacol Physiol. 2002; 29(10):859-66. DOI: 10.1046/j.1440-1681.2002.03756.x. View

Peng Q, Matsuda T, Hirst S . Signaling pathways regulating interleukin-13-stimulated chemokine release from airway smooth muscle. Am J Respir Crit Care Med. 2003; 169(5):596-603. DOI: 10.1164/rccm.200307-888OC. View

Dickensheets H, Venkataraman C, Schindler U, Donnelly R . Interferons inhibit activation of STAT6 by interleukin 4 in human monocytes by inducing SOCS-1 gene expression. Proc Natl Acad Sci U S A. 1999; 96(19):10800-5. PMC: 17963. DOI: 10.1073/pnas.96.19.10800. View

LAPORTE J, Moore P, Baraldo S, Jouvin M, Church T, Schwartzman I . Direct effects of interleukin-13 on signaling pathways for physiological responses in cultured human airway smooth muscle cells. Am J Respir Crit Care Med. 2001; 164(1):141-8. DOI: 10.1164/ajrccm.164.1.2008060. View

10.

Zuyderduyn S, Hiemstra P, Rabe K . TGF-beta differentially regulates TH2 cytokine-induced eotaxin and eotaxin-3 release by human airway smooth muscle cells. J Allergy Clin Immunol. 2004; 114(4):791-8. DOI: 10.1016/j.jaci.2004.06.037. View

11.

Heller N, Matsukura S, Georas S, Boothby M, Rothman P, Stellato C . Interferon-gamma inhibits STAT6 signal transduction and gene expression in human airway epithelial cells. Am J Respir Cell Mol Biol. 2004; 31(5):573-82. DOI: 10.1165/rcmb.2004-0195OC. View

12.

Dickensheets H, Vazquez N, Sheikh F, Gingras S, Murray P, Ryan J . Suppressor of cytokine signaling-1 is an IL-4-inducible gene in macrophages and feedback inhibits IL-4 signaling. Genes Immun. 2006; 8(1):21-7. DOI: 10.1038/sj.gene.6364352. View

13.

Faffe D, Whitehead T, Moore P, Baraldo S, Flynt L, Bourgeois K . IL-13 and IL-4 promote TARC release in human airway smooth muscle cells: role of IL-4 receptor genotype. Am J Physiol Lung Cell Mol Physiol. 2003; 285(4):L907-14. DOI: 10.1152/ajplung.00120.2003. View

14.

Yoshida M, Leigh R, Matsumoto K, Wattie J, Ellis R, OByrne P . Effect of interferon-gamma on allergic airway responses in interferon-gamma-deficient mice. Am J Respir Crit Care Med. 2002; 166(4):451-6. DOI: 10.1164/rccm.200202-095OC. View

15.

COHN L, Tepper J, Bottomly K . IL-4-independent induction of airway hyperresponsiveness by Th2, but not Th1, cells. J Immunol. 1998; 161(8):3813-6. View

16.

Mentink-Kane M, Cheever A, Thompson R, Hari D, Kabatereine N, Vennervald B . IL-13 receptor alpha 2 down-modulates granulomatous inflammation and prolongs host survival in schistosomiasis. Proc Natl Acad Sci U S A. 2003; 101(2):586-90. PMC: 327191. DOI: 10.1073/pnas.0305064101. View

17.

Kuperman D, Schofield B, Wills-Karp M, Grusby M . Signal transducer and activator of transcription factor 6 (Stat6)-deficient mice are protected from antigen-induced airway hyperresponsiveness and mucus production. J Exp Med. 1998; 187(6):939-48. PMC: 2212182. DOI: 10.1084/jem.187.6.939. View

18.

Hirst S, Hallsworth M, Peng Q, Lee T . Selective induction of eotaxin release by interleukin-13 or interleukin-4 in human airway smooth muscle cells is synergistic with interleukin-1beta and is mediated by the interleukin-4 receptor alpha-chain. Am J Respir Crit Care Med. 2002; 165(8):1161-71. DOI: 10.1164/ajrccm.165.8.2107158. View

19.

Grunig G, Warnock M, Wakil A, Venkayya R, Brombacher F, Rennick D . Requirement for IL-13 independently of IL-4 in experimental asthma. Science. 1998; 282(5397):2261-3. PMC: 3897229. DOI: 10.1126/science.282.5397.2261. View

20.

Moore P, Church T, Chism D, Panettieri Jr R, Shore S . IL-13 and IL-4 cause eotaxin release in human airway smooth muscle cells: a role for ERK. Am J Physiol Lung Cell Mol Physiol. 2002; 282(4):L847-53. DOI: 10.1152/ajplung.00245.2001. View