IL-12 plays a critical role in the development of cell-mediated immune responses and in the pathogenesis of inflammatory and autoimmune disorders. Dexamethasone (DXM), an anti-inflammatory glucocorticoid, has been shown to inhibit IL-12p40 production in LPS-stimulated monocytic cells. In this study, we investigated the molecular mechanism by which DXM inhibits IL-12p40 production by studying the role of the mitogen-activated protein kinases (MAPKs), and the key transcription factors involved in human IL-12p40 production in LPS-stimulated monocytic cells. A role for c-Jun N-terminal kinase (JNK) MAPK in LPS-induced IL-12p40 regulation in a promonocytic THP-1/CD14 cell line was demonstrated by using specific inhibitors of JNK activation, SP600125 and a dominant-negative stress-activated protein/extracellular signal-regulated kinase kinase-1 mutant. To identify transcription factors regulating IL-12p40 gene transcription, extensive deletion analyses of the IL-12p40 promoter was performed. The results revealed the involvement of a sequence encompassing the AP-1-binding site, in addition to that of NF-κB. The role of AP-1 in IL-12p40 transcription was confirmed by using antisense c-fos and c-jun oligonucleotides. Studies conducted to understand the regulation of AP-1 and NF-κB activation by JNK MAPK revealed that both DXM and SP600125 inhibited IL-12p40 gene transcription by inhibiting the activation of AP-1 and NF-κB transcription factors as revealed by luciferase reporter and gel mobility shift assays. Taken together, our results suggest that DXM may inhibit IL-12p40 production in LPS-stimulated human monocytic cells by down-regulating the activation of JNK MAPK, the AP-1, and NF-κB transcription factors.

The SWI/SNF complex participates as a co-activator in the transcriptional regulation of certain genes. Conversely, we and others have recently established that Brg1 and Brm, the central components of SWI/SNF, act instead as co-repressors for E2F-mediated transcriptional repression, and for the transcription of certain other promoters. We report here that Brg-1 and Brm can switch their mode of function at same promoter between activation and repression by ligand-directed differential coordination with BAF155, BAF170, HDAC1, p300 and prohibitin. This ligand and context-dependent reprogramming of the SWI/SNF complex allows it to differentially serve as either a co-repressor or a co-activator of transcription at the same promoter.

HIC1 is a newly discovered tumor suppressor and transcriptional repressor that is frequently silenced in human tumors. HIC1 protein expression has been linked to better outcomes in breast cancers. The molecular mechanism underlying HIC1-mediated transcriptional and growth suppression, and the relevant targets of HIC1-mediated transcriptional modulation, is currently unclear. We have identified an HIC1 DNA-binding site in E2F-responsive gene promoters and demonstrate that HIC1 targets E2F-responsive genes for transcriptional regulation and growth suppression. We and others have recently discovered that Brg1, a central component of the SWI/ SNF chromatin-remodeling family, is required for the transcriptional regulation of multiple cell cycle controlrelated genes, including E2F-responsive promoters. We studied HIC1 interactions with, and dependence upon, Brg1 activity, and found that HIC1 can recruit Brg1 to E2F-responsive promoters and that its transcriptional repression of these genes is dependent upon Brg1. These data indicate that HIC1 is a central molecule in a novel mechanism controlling cell growth and that the disruption of this HIC1-mediated pathway may lead to abnormal cell proliferation and, ultimately, cancer.