Intrinsic cleavage of receptor-interacting protein kinase-1 by caspase-6

Necroptosis is a form of programmed cell death that occurs in the absence of caspase activation and depends on the activity of the receptor-interacting protein kinases. Inactivation of these kinases by caspase-mediated cleavage has been shown to be essential for successful embryonic development, survival and activation of certain cell types. The initiator of extrinsic apoptosis, caspase-8, which has a pro-death as well as a pro-life function, has been assigned this role. In the present study we demonstrate that caspase-6, an executioner caspase, performs this role during apoptosis induced through the intrinsic pathway. In addition, we demonstrate that in the absence of caspase activity, intrinsic triggers of apoptosis induce the receptor-interacting-kinase-1-dependent production of pro-inflammatory cytokines. We show that ubiquitously expressed caspase-6 has a supporting role in apoptosis by cleaving this kinase, thus preventing production of inflammatory cytokines as well as inhibiting the necroptotic pathway. These findings shed new light on the regulation of necroptosis as well as cell death in an inflammatory environment wherein cells receive both intrinsic and extrinsic death signals

Multiple chemical sensitivity and idiopathic environmental intolerance (part two)

Multiple chemical sensitivity/idiopathic environmental intolerance (MCS/IEI) is a commonly used diagnostic term for a group of symptoms without apparent organic basis. The symptoms are characteristic of dysfunction in multiple organ systems. They wax and wane fluctuate according to exposure to low levels of chemical agents in the patient's environment, and sometimes begin after a distinct environmental change or injury such an industrial accident or chemical introduced after remodeling. Although traditional medical organizations have not agreed on a definition for this syndrome, it is being increasingly recognized and makes up an increasing percentage of the caseload at occupational/environmental medical clinics