ABSTRACT
The cAMP response element modulator (CREM)alpha is a widely expressed transcriptional repressor that is important for the termination of the T cell immune response and contributes to the abnormal T cell function in patients with systemic lupus erythematosus. We present evidence that APCs of Crem(-/-) mice express increased amounts of the costimulatory molecule CD86 and induce enhanced Ag-dependent and Ag-independent T cell proliferation. Similarly, human APCs in which CREMalpha was selectively suppressed expressed more CD86 on the surface membrane. CREMalpha was found to bind to the CD86 promoter and suppressed its activity. Transfer of APCs from Crem(-/-) mice into naive mice facilitated a significantly stronger contact dermatitis response compared with mice into which APCs from Crem(+/+) mice had been transferred. We conclude that CREMalpha is an important negative regulator of costimulation and APC-dependent T cell function both in vitro and in vivo.
Subject(s)
Antigen-Presenting Cells/immunology , B7-2 Antigen/immunology , Cyclic AMP Response Element Modulator/immunology , Gene Expression Regulation/immunology , Animals , Antigen-Presenting Cells/metabolism , B7-2 Antigen/genetics , B7-2 Antigen/metabolism , Cyclic AMP Response Element Modulator/genetics , Cyclic AMP Response Element Modulator/metabolism , Dermatitis, Contact/immunology , Dermatitis, Contact/pathology , Flow Cytometry , Gene Expression/immunology , Humans , Lymphocyte Activation/immunology , Mice , Mice, Transgenic , Oligonucleotide Array Sequence Analysis , Promoter Regions, Genetic , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocytes/immunologyABSTRACT
Tumor necrosis factor alpha (TNFalpha) is a pleiotropic cytokine involved in apoptotic cell death, cellular proliferation, differentiation, inflammation, and tumorigenesis. In tumors it is secreted by tumor associated macrophages and can have both pro- and anti-tumorigenic effects. To identify genes regulated by TNFalpha, we performed a gene trap screen in the mammary carcinoma cell line MCF-7 and recovered 64 unique, TNFalpha-induced gene trap integration sites. Among these were the genes coding for the zinc finger protein ZC3H10 and for the transcription factor grainyhead-like 3 (GRHL3). In line with the dual effects of TNFalpha on tumorigenesis, we found that ZC3H10 inhibits anchorage independent growth in soft agar suggesting a tumor suppressor function, whereas GRHL3 strongly stimulated the migration of endothelial cells which is consistent with an angiogenic, pro-tumorigenic function.