IL-4 and TGF-beta 1 Counterbalance One Another While Regulating Mast Cell Homeostasis

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2010 Mar 23

PMID 20304823

Citations 26

Authors

Matthew R Macey

Jamie L Sturgill

Johanna K Morales

Yves T Falanga

Joshua Morales

Sarah K Norton

Nitin Yerram

Hoon Shim

Josephine Fernando

Alasdair M Gifillan

Gregorio Gomez

Lawrence Schwartz

Carole Oskeritzian

Sarah Spiegel

Daniel Conrad

John J Ryan

Affiliations

Soon will be listed here.

Abstract

Mast cell responses can be altered by cytokines, including those secreted by Th2 and regulatory T cells (Treg). Given the important role of mast cells in Th2-mediated inflammation and recent demonstrations of Treg-mast cell interactions, we examined the ability of IL-4 and TGF-beta1 to regulate mast cell homeostasis. Using in vitro and in vivo studies of mouse and human mast cells, we demonstrate that IL-4 suppresses TGF-beta1 receptor expression and signaling, and vice versa. In vitro studies demonstrated that IL-4 and TGF-beta1 had balancing effects on mast cell survival, migration, and FcepsilonRI expression, with each cytokine cancelling the effects of the other. However, in vivo analysis of peritoneal inflammation during Nippostrongylus brasiliensis infection in mice revealed a dominant suppressive function for TGF-beta1. These data support the existence of a cytokine network involving the Th2 cytokine IL-4 and the Treg cytokine TGF-beta1 that can regulate mast cell homeostasis. Dysregulation of this balance may impact allergic disease and be amenable to targeted therapy.

Citing Articles

Monocyte-derived Langerhans cells express Delta-like 4 induced by peptidoglycan and interleukin-4 mediated suppression.

Ono R, Maeda K, Tanioka T, Isozaki T Front Immunol. 2025; 16:1532620.

PMID: 40018044 PMC: 11865044. DOI: 10.3389/fimmu.2025.1532620.

Shrimp allergen extract immunotherapy induces prolonged immune tolerance in a gastro-food allergy mouse model.

Marhaeny H, Rohmah L, Pratama Y, Kasatu S, Miatmoko A, Addimaysqi R PLoS One. 2024; 19(12):e0315312.

PMID: 39729447 PMC: 11676511. DOI: 10.1371/journal.pone.0315312.

Interleukin 4 and cancer resistance in glioblastoma multiforme.

Detchou D, Barrie U Neurosurg Rev. 2024; 47(1):448.

PMID: 39164434 DOI: 10.1007/s10143-024-02695-4.

Revisiting regulatory T cells as modulators of innate immune response and inflammatory diseases.

Ou Q, Power R, Griffin M Front Immunol. 2023; 14:1287465.

PMID: 37928540 PMC: 10623442. DOI: 10.3389/fimmu.2023.1287465.

Drug repositioning of anti-microbial agent nifuratel to treat mast cell-mediated allergic responses.

Lee J, Choi M, Min K, Jo M, Kim Y, Kim H Int J Immunopathol Pharmacol. 2023; 37:3946320231202349.

PMID: 37706235 PMC: 10503296. DOI: 10.1177/03946320231202349.

References

Bissonnette E, Enciso J, Befus A . TGF-beta1 inhibits the release of histamine and tumor necrosis factor-alpha from mast cells through an autocrine pathway. Am J Respir Cell Mol Biol. 1997; 16(3):275-82. DOI: 10.1165/ajrcmb.16.3.9070612. View

Cai J, Falanga V, Taylor J, Chin Y . Transforming growth factor-beta receptor binding and function are decreased in psoriatic dermal endothelium. J Invest Dermatol. 1996; 106(2):225-31. DOI: 10.1111/1523-1747.ep12340553. View

Zhao W, Gomez G, Yu S, Ryan J, Schwartz L . TGF-beta1 attenuates mediator release and de novo Kit expression by human skin mast cells through a Smad-dependent pathway. J Immunol. 2008; 181(10):7263-72. PMC: 2645416. DOI: 10.4049/jimmunol.181.10.7263. View

Pillemer B, Qi Z, Melgert B, Oriss T, Ray P, Ray A . STAT6 activation confers upon T helper cells resistance to suppression by regulatory T cells. J Immunol. 2009; 183(1):155-63. PMC: 2754746. DOI: 10.4049/jimmunol.0803733. View

Toru H, Ra C, Nonoyama S, Suzuki K, Yata J, Nakahata T . Induction of the high-affinity IgE receptor (Fc epsilon RI) on human mast cells by IL-4. Int Immunol. 1996; 8(9):1367-73. DOI: 10.1093/intimm/8.9.1367. View

Mantel P, Kuipers H, Boyman O, Rhyner C, Ouaked N, Ruckert B . GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells. PLoS Biol. 2007; 5(12):e329. PMC: 2222968. DOI: 10.1371/journal.pbio.0050329. View

Kikuchi H, Hanazawa S, Takeshita A, Nakada Y, Yamashita Y, Kitano S . Interleukin-4 acts as a potent stimulator for expression of monocyte chemoattractant JE/MCP-1 in mouse peritoneal macrophages. Biochem Biophys Res Commun. 1994; 203(1):562-9. DOI: 10.1006/bbrc.1994.2219. View

Shevach E . Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity. 2009; 30(5):636-45. DOI: 10.1016/j.immuni.2009.04.010. View

Ryan J, Kashyap M, Bailey D, Kennedy S, Speiran K, Brenzovich J . Mast cell homeostasis: a fundamental aspect of allergic disease. Crit Rev Immunol. 2007; 27(1):15-32. DOI: 10.1615/critrevimmunol.v27.i1.20. View

10.

Sherman M, Powell D, Brown M . IL-4 induces the proteolytic processing of mast cell STAT6. J Immunol. 2002; 169(7):3811-8. DOI: 10.4049/jimmunol.169.7.3811. View

11.

Rosbottom A, Knight P, McLachlan G, Thornton E, Wright S, Miller H . Chemokine and cytokine expression in murine intestinal epithelium following Nippostrongylus brasiliensis infection. Parasite Immunol. 2002; 24(2):67-75. DOI: 10.1046/j.0141-9838.2001.00437.x. View

12.

de Groot R, Coffer P, Koenderman L . Regulation of proliferation, differentiation and survival by the IL-3/IL-5/GM-CSF receptor family. Cell Signal. 1998; 10(9):619-28. DOI: 10.1016/s0898-6568(98)00023-0. View

13.

Ryan J, DESIMONE S, Klisch G, Shelburne C, McReynolds L, Han K . IL-4 inhibits mouse mast cell Fc epsilonRI expression through a STAT6-dependent mechanism. J Immunol. 1998; 161(12):6915-23. View

14.

Furuichi K, Rivera J, ISERSKY C . The receptor for immunoglobulin E on rat basophilic leukemia cells: effect of ligand binding on receptor expression. Proc Natl Acad Sci U S A. 1985; 82(5):1522-5. PMC: 397295. DOI: 10.1073/pnas.82.5.1522. View

15.

Piconese S, Gri G, Tripodo C, Musio S, Gorzanelli A, Frossi B . Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation. Blood. 2009; 114(13):2639-48. DOI: 10.1182/blood-2009-05-220004. View

16.

Gordon J, Katira A, Strain A, Gillis S . Inhibition of interleukin 4-promoted CD23 production in human B lymphocytes by transforming growth factor-beta, interferons or anti-CD19 antibody is overriden on engaging CD40. Eur J Immunol. 1991; 21(8):1917-22. DOI: 10.1002/eji.1830210821. View

17.

Wills-Karp M, Finkelman F . Untangling the complex web of IL-4- and IL-13-mediated signaling pathways. Sci Signal. 2008; 1(51):pe55. PMC: 4446705. DOI: 10.1126/scisignal.1.51.pe55. View

18.

Shimoda K, van Deursen J, Sangster M, Sarawar S, Carson R, Tripp R . Lack of IL-4-induced Th2 response and IgE class switching in mice with disrupted Stat6 gene. Nature. 1996; 380(6575):630-3. DOI: 10.1038/380630a0. View

19.

Kaplan M, Schindler U, Smiley S, Grusby M . Stat6 is required for mediating responses to IL-4 and for development of Th2 cells. Immunity. 1996; 4(3):313-9. DOI: 10.1016/s1074-7613(00)80439-2. View

20.

Kulka M, Metcalfe D . High-resolution tracking of cell division demonstrates differential effects of TH1 and TH2 cytokines on SCF-dependent human mast cell production in vitro: correlation with apoptosis and Kit expression. Blood. 2004; 105(2):592-9. DOI: 10.1182/blood-2004-07-2838. View