The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor

AbstractThe 60 kDa tumor necrosis factor receptor (TNFR60) is regarded as the major signal transducer of TNF-induced cellular responses, whereas the signal capacity and role of the 80 kDa TNFR (TNFR80) remain largely undefined. We show here that the transmembrane form of TNF is superior to soluble TNF in activating TNFR80 in various systems such as T cell activation, thymocyte proliferation, and granulocyte/macrophage colony-stimulating factor production. Intriguingly, activation of TNFR80 by membrane TNF can lead to qualitatively different TNF responses such as rendering resistant tumor cells sensitive to TNF-mediated cytotoxicity. This study demonstrates that the diversity of TNF effects can be controlled through the differential sensitivity of TNFR80 for the two forms of TNF and suggests an important physiological role for TNFR80 in local inflammatory responses

TNF receptors TR60 and TR80 can mediate apoptosis via induction of distinct signal pathways

TNF membrane receptors are usually co-expressed in many tissues but their relative contribution to cellular TNF responses is for most situations unknown. In a TNF cytotoxicity model of KYM-1, a human rhabdomyosarcoma cell line, we recently demonstrated that each of the two TNFRs is on its own capable of inducing cell death. Here we show that both receptors are able to induce apoptosis, as revealed from a similar onset of DNA fragmentation and typical morphologic criteria. To obtain additional information about the signaling pathways involved in TR60- and TR80-induced programmed cell death, we have used a series of selective inhibitors of intracellular signaling molecules. The overall pattern emerging from these experiments provides strong evidence for distinct signal pathway usage of TR60 and TR80, indicating protein kinase(s)-mediated control of TR60 signaling and a tight linkage of TR80 to arachidonate metabolism. The subsequent establishment of KYM-1·derived cell lines that display TNFR selective resistance further supports a segregation of TR60 and TR80 signaling pathways for induction of apoptotic cell death. Moreover, these results demonstrate an independent control of the distinct signaling cascades used by TR60 and TR80. This allows a highly flexible regulation of a cellular TNF response in those cases in which both receptors contribute to overall TNF responsiveness

Assessment of the performance of CORDEX Regional Climate Models in Simulating Eastern Africa Rainfall

This study evaluates the ability of 10 regional climate models (RCMs) from the Coordinated Regional Climate Downscaling Experiment (CORDEX) in simulating the characteristics of rainfall patterns over eastern Africa. The seasonal climatology, annual rainfall cycles, and interannual variability of RCM output have been assessed over three homogeneous subregions against a number of observational datasets. The ability of the RCMs in simulating large-scale global climate forcing signals is further assessed by compositing the El Niño–Southern Oscillation (ENSO) and Indian Ocean dipole (IOD) events. It is found that most RCMs reasonably simulate the main features of the rainfall climatology over the three subregions and also reproduce the majority of the documented regional responses to ENSO and IOD forcings. At the same time the analysis shows significant biases in individual models depending on subregion and season; however, the ensemble mean has better agreement with observation than individual models. In general, the analysis herein demonstrates that the multimodel ensemble mean simulates eastern Africa rainfall adequately and can therefore be used for the assessment of future climate projections for the region