Receptor crosslinking of T-cell hybridomas induces cell activation followed by apoptosis. This activation-induced cell death requires de novo synthesis of RNA and proteins, but the actual gene products that provide the death signal have not been identified. We show here that receptor crosslinking induces Fas ligand and upregulates Fas, and that the ensuing engagement of Fas by Fas ligand activates the cell-death programme. Cell death, but not activation, can be selectively prevented by a soluble Fas-immunoglobulin fusion protein. Thus, Fas and Fas ligand are the death-gene products, and their interaction accounts for the molecular mechanism of activation-induced T-cell death.

IL-10 producing regulatory type 1 (TR1) T cells are instrumental in the prevention of tissue inflammation, autoimmunity and graft-versus-host disease. The transcription factor c-Maf is essential for TR1 induction of IL-10, but the molecular mechanisms leading to the development of these cells remain incompletely understood. We demonstrate that the ligand–activated transcription factor aryl hydrocarbon receptor (AhR) induced by IL-27, synergizes with c-Maf to promote the development of TR1 cells. Upon T cell activation under TR1-skewing conditions, the AhR binds to c-Maf and promotes the transactivation of both Il10 and Il21 promoters, resulting in the generation of TR1 cells and amelioration of experimental autoimmune encephalomyelitis. Manipulation of AhR signaling could therefore be beneficial in the resolution of excessive inflammatory responses.

Apoptosis of the WEHI 231 immature B cell lymphoma line following membrane interaction with an antibody against the surface IgM chains (anti‐IgM) is preceded by dramatic changes in Nuclear Factor‐kappaB (NF‐kappaB)/ Rel binding activities. An early transient increase in NF‐kappaB/Rel binding is followed by a significant decrease in intensity below basal levels. Here we have explored the role of these changes in Rel‐related factors in B cell apoptosis. Treatment of WEH1 231 cells with N‐tosyl‐L‐phenylalanine chloromethyl ketone (TPCK), a protease inhibitor which prevents degradation of the inhibitor of NF‐kappaB (IkappaB)‐alpha, or with low doses of pyrrolidinedithiocarbamate (PDTC) selectively inhibited NF‐kappaB/Rel factor binding and induced apoptosis. Bcl‐XL expression protected WEHI 231 cells from apoptosis induced by these agents. Microinjection of WEHI 231 cells with either IkappaB‐alpha‐GST protein or a c‐Rel affinity‐purified antibody induced apoptosis. Ectopic c‐Rel expression ablated apoptosis induced by TPCK or anti‐IgM. Treatment of BALENLM 17 and A20 B lymphoma cells or normal murine splenic B lymphocytes with either TPCK or PDTC also resulted in apoptosis. These findings indicate that the drop in NF‐kappaB/Rel binding following anti‐IgM treatment activates apoptosis of WEHI 231 cells; furthermore, they implicate the NF‐kappaB/Rel family in control of apoptosis of normal and transformed B cells.

The gut microbiota plays a significant role in the progression of fatty liver disease; however, the mediators and their mechanisms remain to be elucidated. Comparing metabolite profile differences between germ-free and conventionally raised mice against differences between mice fed a low- and high-fat diet (HFD), we identified tryptamine and indole-3-acetate (I3A) as metabolites that depend on the microbiota and are depleted under a HFD. Both metabolites reduced fatty-acid- and LPS-stimulated production of pro-inflammatory cytokines in macrophages and inhibited the migration of cells toward a chemokine, with I3A exhibiting greater potency. In hepatocytes, I3A attenuated inflammatory responses under lipid loading and reduced the expression of fatty acid synthase and sterol regulatory element-binding protein-1c. These effects were abrogated in the presence of an aryl-hydrocarbon receptor (AhR) antagonist, indicating that the effects are AhR dependent. Our results suggest that gut microbiota could influence inflammatory responses in the liver through metabolites engaging host receptors.

Polycyclic aromatic hydrocarbons (PAHs) are toxic chemicals released into the environment by fossil fuel combustion. Moreover, a primary route of human exposure to PAHs is tobacco smoke. Oocyte destruction and ovarian failure occur in PAH-treated mice, and cigarette smoking causes early menopause in women. In many cells, PAHs activate the aromatic hydrocarbon receptor (Ahr), a member of the Per-Arnt-Sim family of transcription factors. The Ahr is also activated by dioxin, one of the most intensively studied environmental contaminants. Here we show that an exposure of mice to PAHs induces the expression of Bax in oocytes, followed by apoptosis. Ovarian damage caused by PAHs is prevented by Ahr or Bax inactivation. Oocytes microinjected with a Bax promoter-reporter construct show Ahr-dependent transcriptional activation after PAH, but not dioxin, treatment, consistent with findings that dioxin is not cytotoxic to oocytes. This difference in the action of PAHs versus dioxin is conveyed by a single base pair flanking each Ahr response element in the Bax promoter. Oocytes in human ovarian biopsies grafted into immunodeficient mice also accumulate Bax and undergo apoptosis after PAH exposure in vivo. Thus, Ahr-driven Bax transcription is a novel and evolutionarily conserved cell-death signaling pathway responsible for environmental toxicant-induced ovarian failure.

During progression of an in situ to an invasive cancer, epithelial cells lose expression of proteins that promote cell-cell contact, and acquire mesenchymal markers, which promote cell migration and invasion. These events bear extensive similarities to the process of epithelial to mesenchymal transition (EMT), which has been recognized for several decades as critical feature of embryogenesis. The NF-kB family of transcription factors plays pivotal roles in both promoting and maintaining an invasive phenotype. After briefly describing the NF-kB family and its role in cancer, in this review we will first describe studies elucidating the functions of NF-kB in transcription of master regulator genes that repress an epithelial phenotype. In the second half, we discuss the roles of NF-kB in control of mesenchymal genes critical for promoting and maintaining an invasive phenotype. Overall, NF-kB is identified as a key target in prevention and in the treatment of invasive carcinomas.

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