The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor family of transcription factors, a large and diverse group of proteins that mediate ligand-dependent transcriptional activation and repression. Expression of PPAR-gamma is an early and pivotal event in the differentiation of adipocytes. Several agents that promote differentiation of fibroblast lines into adipocytes have been shown to be PPAR-gamma agonists, including several prostanoids, of which 15-deoxy-delta-prostaglandin J2 is the most potent, as well as members of a new class of oral antidiabetic agents, the thiazolidinediones, and a variety of non-steroidal anti-inflammatory drugs (NSAIDs). Here we show that PPAR-gamma agonists suppress monocyte elaboration of inflammatory cytokines at agonist concentrations similar to those found to be effective for the promotion of adipogenesis. Inhibition of cytokine production may help to explain the incremental therapeutic benefit of NSAIDs observed in the treatment of rheumatoid arthritis at plasma drug concentrations substantially higher than are required to inhibit prostaglandin G/H synthase (cyclooxygenase).

The CD95 (Fas/APO‐1) and tumor necrosis factor (TNF) receptor pathways share many similarities, including a common reliance on proteins containing ‘death domains’ for elements of the membrane‐proximal signal relay. We have created mutant cell lines that are unable to activate NF‐kappaB in response to TNF. One of the mutant lines lacks RIP, a 74 kDa Ser/Thr kinase originally identified by its ability to associate with Fas/APO‐1 and induce cell death. Reconstitution of the line with RIP restores responsiveness to TNF. The RIP‐deficient cell line is susceptible to apoptosis initiated by anti‐CD95 antibodies. An analysis of cells reconstituted with mutant forms of RIP reveals similarities between the action of RIP and FADD/MORT‐1, a Fas‐associated death domain protein.

CASPASE 8 initiates apoptosis downstream of TNF death receptors by undergoing autocleavage and processing the executioner CASPASE 31. However, the dominant function of CASPASE 8 is to transmit a pro-survival signal that suppresses programmed necrosis (or necroptosis) mediated by RIPK1 and RIPK32–6 during embryogenesis and hematopoiesis7–9. Suppression of necrotic cell death by CASPASE 8 requires its catalytic activity but not the autocleavage essential for apoptosis10, however, the key substrate processed by CASPASE 8 to block necrosis has been elusive. A key substrate must meet three criteria: (1) it must be essential for programmed necrosis; (2) it must be cleaved by CASPASE 8 in situations where CASPASE 8 is blocking necrosis; and (3) mutation of the CASPASE 8 processing site on the substrate should convert a pro-survival response to necrotic death without the need for CASPASE 8 inhibition. We now identify CYLD as a novel substrate for CASPASE 8 that satisfies these criteria. Upon TNF stimulation, CASPASE 8 cleaves CYLD to generate a survival signal. In contrast, loss of CASPASE 8 prevented CYLD degradation resulting in necrotic death. A CYLD substitution mutation at D215 that cannot be cleaved by CASPASE 8 switches cell survival to necrotic cell death in response to TNF.

On detecting viral RNAs, the RNA helicase retinoic acid-inducible gene I (RIG-I) activates the interferon regulatory factor 3 (IRF3) signalling pathway to induce type I interferon (IFN) gene transcription. How this antiviral signalling pathway might be negatively regulated is poorly understood. Microarray and bioinformatic analysis indicated that the expression of RIG-I and that of the tumour suppressor CYLD (cylindromatosis), a deubiquitinating enzyme that removes Lys 63-linked polyubiquitin chains, are closely correlated, suggesting a functional association between the two molecules. Ectopic expression of CYLD inhibits the IRF3 signalling pathway and IFN production triggered by RIG-I; conversely, CYLD knockdown enhances the response. CYLD removes polyubiquitin chains from RIG-I as well as from TANK binding kinase 1 (TBK1), the kinase that phosphorylates IRF3, coincident with an inhibition of the IRF3 signalling pathway. Furthermore, CYLD protein level is reduced in the presence of tumour necrosis factor and viral infection, concomitant with enhanced IFN production. These findings show that CYLD is a negative regulator of RIG-I-mediated innate antiviral response. Keywords: cylindromatosis; interferon; IRF3; RIG-I; ubiquitin EMBO reports (2008) 9, 930-936.