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Abstract
The cellular inhibitor of apoptosis 2 (cIAP2/HIAP1) is a potent inhibitor of apoptotic death. In contrast to the other members of the IAP family, cIAP2 is transcriptionally inducible by nuclear factor-κB in response to multiple triggers. We demonstrate here that cIAP2−/− mice exhibit profound resistance to lipopolysaccharide (LPS)-induced sepsis, specifically because of an attenuated inflammatory response. We show that LPS potently upregulates cIAP2 in macrophages and that cIAP2−/− macrophages are highly susceptible to apoptosis in a LPS-induced proinflammatory environment. Hence, cIAP2 is critical in the maintenance of a normal innate immune inflammatory response.
We thank L. Kelly, C. McRoberts, and M. St. Jean for technical support.
This study was supported by grants from the Canada Foundation for Innovation, Ontario Research and Development Challenge Fund, Canadian Institutes of Health Research (CIHR), the Canadian Networks of Centers of Excellence, Muscular Dystrophy Association and the Howard Hughes Medical Institute (HHMI). M.H. is a CIHR New Investigator. R.G.K. is a recipient of an MRC Senior Scientist Award, a Fellow of the Royal Society of Canada, and an HHMI International Research Scholar.