PT - JOURNAL ARTICLE AU - Ratnadeep Mukherjee AU - Diwakar Kumar Singh AU - Pijus Kanti Barman AU - Birendra Kumar Prusty AU - Pravat Thatoi AU - Rina Tripathy AU - Bidyut Kumar Das AU - Balachandran Ravindran TI - A novel polymorphism in nitric oxide synthase interacting protein (NOSIP) modulates nitric oxide synthesis and influences mortality in human sepsis AID - 10.1101/038398 DP - 2016 Jan 01 TA - bioRxiv PG - 038398 4099 - http://biorxiv.org/content/early/2016/02/02/038398.short 4100 - http://biorxiv.org/content/early/2016/02/02/038398.full AB - Nitric oxide performs a wide variety of versatile functions in the immune system. But it’s precise role in the pathogenesis of acute inflammation and sepsis is still controversial. In the present study, we demonstrate a novel mutation in nitric oxide synthase interacting protein (NOSIP) and its association with mortality in sepsis. We also show direct physical interaction of NOSIP with inducible nitric oxide synthase (iNOS), and demonstrate that differences in expression of NOSIP could influence differential induction of nitric oxide by monocytes/macrophages among species. Observations made in mice deficient in iNOS suggest that protective mechanism of nitric oxide in LPS induced inflammation is probably mediated by inhibiton of IL-1β synthesis. Differential nitric oxide production between mice and humans is also reflected upon IL-1β production between the species, where a clear inverse relationship emerges between nitric oxide and IL-1β. Thus, our study reveals NOSIP as an important regulator of inflammation by virtue of its ability to influence nitric oxide mediated inhibition of IL-1β synthesis and has opened up new avenues for therapeutic strategies against sepsis.