Type I IFNs have been demonstrated to be critical in the induction of septic shock initiated by lipopolysaccharide (LPS) a cell wall component derived from gram negative bacterium. In contrast, IFNs have been shown to have a protective role in a model of experimental colitis. The contribution of IFNs in septic shock was first demonstrated with the use of mice deficient in signaling components of the type I IFN pathway which turned out to be resistant to LPS challenge. In our initial studies we first wanted to determine whether STAT2 had a role in septic shock. For this we utilized STAT2 deficient mice and compared them to wild type and STAT1 deficient mice for survival and expression of pro-inflammatory cytokines. Our results revealed that STAT2 is a negative regulator in the septic shock response as mice died sooner within 24 hours as compared to STAT1 deficient mice which showed enhanced resistance to LPS next to control mice. Yet more surprising was finding that STAT2 deficient mice produced less TNF and other pro-inflammatory cytokines. This suggests that STAT1 and STAT2 have different functions in the septic shock response. Now we are trying to understand how a deficiency in STAT2 leads to accelerated mortality. At least we can hypothesize that in addition to the pro-inflammatory cytokines TNF and IL-6, there are other mediators whose expression must be upregulated in the absence of STAT2. For our cancer project to define if STAT2 is a tumor suppressor or tumor oncogene, we are using animal models of chemically induced skin and colorectal cancers which are associated with inflammation. This work is in its early stages and within the next few months we will have more detailed information. Thus far with our LPS model of septic shock we have unveiled a novel role for STAT2 that is different from the one described for STAT1. This suggests that STAT2 deficiency has a different biological outcome than STAT1 deficiency, an observation not described before. We hope to learn more about the role of STAT2 in cancer with our current and future experiments.
| Maher, Stephen G; Sheikh, Faruk; Scarzello, Anthony J et al. (2008) IFN-alpha and IFN-lambda differ in their antiproliferative effects and duration of JAK/STAT signaling activity. Cancer Biol Ther 7:nihpa47781 |
