Regulation of IL-4 Expression by the Transcription Factor JunB During T Helper Cell Differentiation

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 1999 Jan 16

PMID 9889198

Citations 150

Authors

B Li

C Tournier

R J Davis

R A Flavell

Affiliations

Soon will be listed here.

Abstract

The molecular basis for restricted cytokine expression by T helper 1 (Th1) and T helper 2 (Th2) cells is unclear. Previous studies found that P1, an element of the interleukin 4 (IL-4) promoter that binds AP-1, is important for Th2-restricted IL-4 expression. Here we show that JunB, but not the other Jun family members, was selectively induced in Th2 cells and not in Th1 cells during differentiation. JunB has previously been considered to be a negative regulator of transcription. However, we show that JunB binds directly to the P1 site and synergizes with c-Maf to activate an IL-4 luciferase reporter gene. JunB-control of IL-4 expression is mediated by the phosphorylation of JunB at Thr102 and -104 by JNK MAP kinase. The synergy between c-Maf and JunB can be attributed to cooperative DNA binding, which is facilitated by JunB phosphorylation. In transgenic mice, elevated JunB levels caused increased expression of several Th2 cytokines in developing Th1 cells. JunB also upregulated IL-4 expression in response to immunization. Thus, the early increase of JunB protein in Th2 cells can provide the specificity for c-Maf in IL-4 expression during T cell development and directs thereby Th2 differentiation.

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References

Seder R, Paul W, Davis M, Fazekas de St Groth B . The presence of interleukin 4 during in vitro priming determines the lymphokine-producing potential of CD4+ T cells from T cell receptor transgenic mice. J Exp Med. 1992; 176(4):1091-8. PMC: 2119379. DOI: 10.1084/jem.176.4.1091. View

Hsieh C, Heimberger A, Gold J, OGarra A, Murphy K . Differential regulation of T helper phenotype development by interleukins 4 and 10 in an alpha beta T-cell-receptor transgenic system. Proc Natl Acad Sci U S A. 1992; 89(13):6065-9. PMC: 49438. DOI: 10.1073/pnas.89.13.6065. View

Abe E, de Waal Malefyt R, Matsuda I, Arai K, Arai N . An 11-base-pair DNA sequence motif apparently unique to the human interleukin 4 gene confers responsiveness to T-cell activation signals. Proc Natl Acad Sci U S A. 1992; 89(7):2864-8. PMC: 48763. DOI: 10.1073/pnas.89.7.2864. View

Li-Weber M, Eder A, Krammer P . T cell-specific negative regulation of transcription of the human cytokine IL-4. J Immunol. 1992; 148(6):1913-8. View

Tugores A, Alonso M, Sanchez-Madrid F, de Landazuri M . Human T cell activation through the activation-inducer molecule/CD69 enhances the activity of transcription factor AP-1. J Immunol. 1992; 148(7):2300-6. View

Alvarez E, Northwood I, Gonzalez F, Latour D, Seth A, Abate C . Pro-Leu-Ser/Thr-Pro is a consensus primary sequence for substrate protein phosphorylation. Characterization of the phosphorylation of c-myc and c-jun proteins by an epidermal growth factor receptor threonine 669 protein kinase. J Biol Chem. 1991; 266(23):15277-85. View

Mosmann T, Cherwinski H, Bond M, Giedlin M, Coffman R . Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol. 1986; 136(7):2348-57. View

Chiu R, Angel P, Karin M . Jun-B differs in its biological properties from, and is a negative regulator of, c-Jun. Cell. 1989; 59(6):979-86. DOI: 10.1016/0092-8674(89)90754-x. View

Schutte J, Viallet J, Nau M, Segal S, Fedorko J, Minna J . jun-B inhibits and c-fos stimulates the transforming and trans-activating activities of c-jun. Cell. 1989; 59(6):987-97. DOI: 10.1016/0092-8674(89)90755-1. View

10.

Ho S, Hunt H, Horton R, Pullen J, Pease L . Site-directed mutagenesis by overlap extension using the polymerase chain reaction. Gene. 1989; 77(1):51-9. DOI: 10.1016/0378-1119(89)90358-2. View

11.

Schreiber E, Matthias P, Muller M, Schaffner W . Rapid detection of octamer binding proteins with 'mini-extracts', prepared from a small number of cells. Nucleic Acids Res. 1989; 17(15):6419. PMC: 318318. DOI: 10.1093/nar/17.15.6419. View

12.

Davis R, Czech M . Tumor-promoting phorbol diesters cause the phosphorylation of epidermal growth factor receptors in normal human fibroblasts at threonine-654. Proc Natl Acad Sci U S A. 1985; 82(7):1974-8. PMC: 397463. DOI: 10.1073/pnas.82.7.1974. View

13.

Smith D, Johnson K . Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase. Gene. 1988; 67(1):31-40. DOI: 10.1016/0378-1119(88)90005-4. View

14.

Davydov I, Krammer P, Li-Weber M . Nuclear factor-IL6 activates the human IL-4 promoter in T cells. J Immunol. 1995; 155(11):5273-9. View

15.

Rooney J, Hoey T, Glimcher L . Coordinate and cooperative roles for NF-AT and AP-1 in the regulation of the murine IL-4 gene. Immunity. 1995; 2(5):473-83. DOI: 10.1016/1074-7613(95)90028-4. View

16.

Gupta S, Campbell D, Derijard B, Davis R . Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science. 1995; 267(5196):389-93. DOI: 10.1126/science.7824938. View

17.

Seder R, Gazzinelli R, Sher A, Paul W . Interleukin 12 acts directly on CD4+ T cells to enhance priming for interferon gamma production and diminishes interleukin 4 inhibition of such priming. Proc Natl Acad Sci U S A. 1993; 90(21):10188-92. PMC: 47739. DOI: 10.1073/pnas.90.21.10188. View

18.

Kamogawa Y, Minasi L, Carding S, Bottomly K, Flavell R . The relationship of IL-4- and IFN gamma-producing T cells studied by lineage ablation of IL-4-producing cells. Cell. 1993; 75(5):985-95. DOI: 10.1016/0092-8674(93)90542-x. View

19.

Paul W, Seder R . Lymphocyte responses and cytokines. Cell. 1994; 76(2):241-51. DOI: 10.1016/0092-8674(94)90332-8. View

20.

Swain S . IL4 dictates T-cell differentiation. Res Immunol. 1993; 144(8):616-20. DOI: 10.1016/s0923-2494(05)80013-6. View