Signal Transducer and Activator of Transcription 6 Controls Chemokine Production and T Helper Cell Type 2 Cell Trafficking in Allergic Pulmonary Inflammation

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2001 May 9

PMID 11342593

Citations 50

Authors

A Mathew

J A MacLean

E DeHaan

A M Tager

F H Green

A D Luster

Affiliations

Soon will be listed here.

Abstract

Antigen-specific CD4 T helper type 2 (Th2) cells play a pivotal role in the induction of allergic asthma, but the mechanisms regulating their recruitment into the airways are unknown. Signal transducer and activator of transcription factor (Stat)6 is a transcription factor essential for Th2 cell differentiation. Here we show that Stat6 also controls Th2 cell recruitment and effector function in allergic inflammation in vivo. To isolate the role of Stat6 in regulating Th2 cell trafficking and effector function from its role in Th2 cell differentiation, we used a murine model of asthma in which in vitro-differentiated Stat6(+/+) antigen-specific Th2 cells were adoptively transferred into naive Stat6(-/-) and Stat6(+/+) mice followed by aerosol antigen challenge. We found that all of the features of asthma, including Th2 cell accumulation, Th2 and eosinophil-active chemokine production, and airway eosinophilia, mucus production, and hyperresponsiveness seen in Stat6(+/+) mice, were dramatically absent in Stat6(-/)- mice that received Stat6(+/)+ antigen-specific Th2 cells. Our findings establish Stat6 as essential for Th2 cell trafficking and effector function and suggest that interruption of Stat6 signaling in resident cells of the lung is a novel approach to asthma therapy.

Citing Articles

Ex Vivo and In Vitro Proteomic Approach to Elucidate the Relevance of IL-4 and IL-10 in Intervertebral Disc Pathophysiology.

Bermudez-Lekerika P, Tseranidou S, Kanelis E, Nuesch A, Crump K, Alexopoulos L JOR Spine. 2025; 8(1):e70048.

PMID: 39931581 PMC: 11808320. DOI: 10.1002/jsp2.70048.

The Impact of the CB Cannabinoid Receptor in Inflammatory Diseases: An Update.

Rakotoarivelo V, Mayer T, Simard M, Flamand N, Di Marzo V Molecules. 2024; 29(14).

PMID: 39064959 PMC: 11279428. DOI: 10.3390/molecules29143381.

Selective Pharmaceutical Inhibition of PARP14 Mitigates Allergen-Induced IgE and Mucus Overproduction in a Mouse Model of Pulmonary Allergic Response.

Eddie A, Chen K, Schenkel L, Swinger K, Molina J, Kunii K Immunohorizons. 2022; 6(7):432-446.

PMID: 35817532 PMC: 10182383. DOI: 10.4049/immunohorizons.2100107.

Exercise and Asthma.

Ding S, Zhong C Adv Exp Med Biol. 2020; 1228:369-380.

PMID: 32342471 DOI: 10.1007/978-981-15-1792-1_25.

G Protein-Coupled Receptors in Asthma Therapy: Pharmacology and Drug Action.

Wendell S, Fan H, Zhang C Pharmacol Rev. 2019; 72(1):1-49.

PMID: 31767622 PMC: 6878000. DOI: 10.1124/pr.118.016899.

References

Stellato C, Matsukura S, Fal A, White J, Beck L, Proud D . Differential regulation of epithelial-derived C-C chemokine expression by IL-4 and the glucocorticoid budesonide. J Immunol. 1999; 163(10):5624-32. View

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

Lloyd C, Delaney T, Nguyen T, Tian J, Martinez-A C, Coyle A . CC chemokine receptor (CCR)3/eotaxin is followed by CCR4/monocyte-derived chemokine in mediating pulmonary T helper lymphocyte type 2 recruitment after serial antigen challenge in vivo. J Exp Med. 2000; 191(2):265-74. PMC: 2195756. DOI: 10.1084/jem.191.2.265. View

DAmbrosio D, Iellem A, Colantonio L, Clissi B, Pardi R, Sinigaglia F . Localization of Th-cell subsets in inflammation: differential thresholds for extravasation of Th1 and Th2 cells. Immunol Today. 2000; 21(4):183-6. DOI: 10.1016/s0167-5699(00)01590-5. View

Chvatchko Y, Hoogewerf A, Meyer A, Alouani S, Juillard P, Buser R . A key role for CC chemokine receptor 4 in lipopolysaccharide-induced endotoxic shock. J Exp Med. 2000; 191(10):1755-64. PMC: 2193157. DOI: 10.1084/jem.191.10.1755. View

Wurster A, Tanaka T, Grusby M . The biology of Stat4 and Stat6. Oncogene. 2000; 19(21):2577-84. DOI: 10.1038/sj.onc.1203485. View

Zhang S, Lukacs N, Lawless V, Kunkel S, Kaplan M . Cutting edge: differential expression of chemokines in Th1 and Th2 cells is dependent on Stat6 but not Stat4. J Immunol. 2000; 165(1):10-4. DOI: 10.4049/jimmunol.165.1.10. View

Sekiya T, Miyamasu M, Imanishi M, Yamada H, Nakajima T, Yamaguchi M . Inducible expression of a Th2-type CC chemokine thymus- and activation-regulated chemokine by human bronchial epithelial cells. J Immunol. 2000; 165(4):2205-13. DOI: 10.4049/jimmunol.165.4.2205. View

Zimmermann N, Hogan S, Mishra A, Brandt E, Bodette T, Pope S . Murine eotaxin-2: a constitutive eosinophil chemokine induced by allergen challenge and IL-4 overexpression. J Immunol. 2000; 165(10):5839-46. DOI: 10.4049/jimmunol.165.10.5839. View

10.

McInnes A, Rennick D . Interleukin 4 induces cultured monocytes/macrophages to form giant multinucleated cells. J Exp Med. 1988; 167(2):598-611. PMC: 2188835. DOI: 10.1084/jem.167.2.598. View

11.

Wilson S, Burd P, Billings P, Martin C, Dorf M . The expression and regulation of a potential lymphokine gene (TCA3) in CD4 and CD8 T cell clones. J Immunol. 1988; 141(5):1563-70. View

12.

Gleich G . The eosinophil and bronchial asthma: current understanding. J Allergy Clin Immunol. 1990; 85(2):422-36. DOI: 10.1016/0091-6749(90)90151-s. View

13.

Weller P . The immunobiology of eosinophils. N Engl J Med. 1991; 324(16):1110-8. DOI: 10.1056/NEJM199104183241607. View

14.

Robinson D, Hamid Q, Ying S, Tsicopoulos A, Barkans J, Bentley A . Predominant TH2-like bronchoalveolar T-lymphocyte population in atopic asthma. N Engl J Med. 1992; 326(5):298-304. DOI: 10.1056/NEJM199201303260504. View

15.

Sanderson C . Interleukin-5, eosinophils, and disease. Blood. 1992; 79(12):3101-9. View

16.

Walker C, Bode E, Boer L, Hansel T, Blaser K, Virchow Jr J . Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage. Am Rev Respir Dis. 1992; 146(1):109-15. DOI: 10.1164/ajrccm/146.1.109. View

17.

Del Prete G, De Carli M, DElios M, Maestrelli P, Ricci M, Fabbri L . Allergen exposure induces the activation of allergen-specific Th2 cells in the airway mucosa of patients with allergic respiratory disorders. Eur J Immunol. 1993; 23(7):1445-9. DOI: 10.1002/eji.1830230707. View

18.

Brusselle G, Kips J, Joos G, Bluethmann H, Pauwels R . Allergen-induced airway inflammation and bronchial responsiveness in wild-type and interleukin-4-deficient mice. Am J Respir Cell Mol Biol. 1995; 12(3):254-9. DOI: 10.1165/ajrcmb.12.3.7873190. View

19.

Foster P, Hogan S, Ramsay A, Matthaei K, Young I . Interleukin 5 deficiency abolishes eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J Exp Med. 1996; 183(1):195-201. PMC: 2192412. DOI: 10.1084/jem.183.1.195. View

20.

Garcia-Zepeda E, Rothenberg M, Ownbey R, Celestin J, Leder P, Luster A . Human eotaxin is a specific chemoattractant for eosinophil cells and provides a new mechanism to explain tissue eosinophilia. Nat Med. 1996; 2(4):449-56. DOI: 10.1038/nm0496-449. View