Recently NF-kB has been shown to have both proapoptotic and antiapoptotic functions. In T cell hybridomas, both T cell activators and glucocorticoids induce apoptosis. Here we show that blockade of NF-kB activity, using a dominant negative IkBa, has opposite effects on these two apoptotic signals. Treatment with PMA plus ionomycin (P/I) results in the upregulation of Fas Ligand (FasL) and induction of apoptosis. Inhibition of NF-kB activity inhibits the P/I mediated induction of FasL mRNA and decreases the level of apoptosis in these cultures, thus establishing NF-kB as a proapoptotic factor in this context. Conversely, inhibition of NF-kB confers a tenfold increase in glucocorticoid mediated apoptosis, establishing that NF-kB also functions as an antiapoptotic factor. We conclude that NF-kB is a context-dependent apoptosis regulator. Our data suggests that NF-kB may function as an antiapoptotic factor in thymocytes while functioning as a proapoptotic factor in mature peripheral T cells.
Glucocorticoids (GCs) function, in part, through the ability of the glucocorticoid receptor (GR) to activate gene expression and in part through the transrepression of AP-1 and NF-B. Here we characterize the effect of GR DNA binding domain (DBD) mutations, previously analyzed for changes in the ability to activate gene expression or transrepress AP-1. We have identified a GR mutant capable of distinguishing between transrepression of NF-B and AP-1. Using circular dichroism spectroscopy, we show that this mutation does not appreciably alter GR DBD conformation, suggesting that functional differences between the mutant and wild type protein are the result of an alteration of a specific interaction surface. These data suggest that transrepression of NF-B and AP-1 occurs through distinct protein-protein interactions and argue against the hypothesis that transrepression occurs through competition for a single coactivator protein. Introduction of these mutations into GC-resistant CEM lymphoblastic T cells restored dexamethasone (DEX)-mediated apoptosis as did wild type GR regardless of whether these mutants were transrepression or activation defective. Thus, DEX-mediated apoptosis in transformed T cells is more complex than originally appreciated. Glucocorticoids (GCs)1 have long been used as anti-inflammatory, immunosuppressive, and chemotherapeutic drugs. Initially, GCs were thought to mediate their therapeutic actions through the transcription of GC-responsive genes (1). This mechanism, however, did little to explain how GCs could inhibit the transcription of many cytokine genes, a critical part of its anti-inflammatory and immunosuppressive actions (2). Subsequently, it was discovered that GR could inhibit the activity of the transcription factor, AP-1, in the absence of a GC-responsive element (GRE) (3)(4)(5)(6). This ability to inhibit directly a transcription factor activity in the absence of a GRE was termed transrepression and was shown to involve a direct physical interaction between GR and AP-1. GCs were also found to inhibit the activity of the transcription factor NF-B (7-11). As NF-B and AP-1 together regulate genes involved in inflammation and immunosuppression, these discoveries allowed the construction of a model for the therapeutic properties of GCs involving both activation and transrepression (12,13).Footprinting studies of the AP-1-driven collagenase promoter after GC treatment showed no change in protein occupancy, suggesting that the GR/AP-1 interaction functions to promote a restructuring of the composition of factors binding to the promoter rather than a simple inhibition of promoter occupancy (14). Domain mapping studies identified the zinc finger DNA binding domain (DBD) of GR as essential for transrepression of AP-1, suggesting that the GR DBD is responsible for both transrepression and activation (4 -6). DNA binding and the subsequent activation of gene expression require the dimerization of GR and its binding to a palindromic GRE (15). Careful dissection of the GR DBD, through mutagenesis...
Objective. To examine the relative importance of tumor necrosis factor receptor I (TNFRI) signaling in the hematopoietic tissue compartment in the progression of collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA).Methods. DBA/1 mice were administered a lethal radiation dose and were then rescued with bone marrow derived from either DBA/1 or TNFRI ؊/؊ mice. CIA was then induced, and disease progression was characterized.Results. Surprisingly, mice with CIA that received TNFRI ؊/؊ donor marrow developed increased disease severity as compared with control mice with CIA. This could not be attributed to an increased primary response to collagen or to the contribution of a non-DBA genetic background. In mice that received TNFRI ؊/؊ bone marrow, histologic markers of advanced disease were evident shortly after initiation of the immune response to collagen and long before clinical evidence of disease. Serum TNF␣ was undetectable, whereas serum interleukin-12 p40 levels were increased, at the end point of the study in mice that received TNFRI ؊/؊ bone marrow.Conclusion. These data raise the intriguing possibility of the existence of an antiinflammatory, TNFRImediated circuit in the hematopoietic compartment. This circuit bears a resemblance to the switch in TNF␣ function that has been observed during the resolution of bacterial infections. These data suggest that TNFRImediated signals in the radioresistant tissues contribute to disease progression, whereas TNFRI-mediated signals in the radiosensitive tissues can contribute to protection from disease. We thus put forward the hypothesis that the degree of response to TNF␣ blockade in RA is dependent in part on the relative genetic strengths of these 2 pathways.
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