Strikingly, a2M/C3-like molecules are not limited to metazoans

ensated. This was supported by studies of islet function in vitro with islets from bIKK mice, in which dysfunction might have been expected. Indeed, results of measurements of GSIS, insulin content, insulin mRNA, and glucose oxidation did not differ from results in control wild-type mice. In addition, when cultured islets were exposed to 15557325 IL-1b or to high glucose levels, no significant differences in insulin content between bIKK and control islets emerged. Transplantation experiments were used to further challenge the bIKK islets. In this situation, the bIKK islets did a little less well, but it is impressive that a minimal number of 150 islets with activated NF-kB were able to cure 36% of the mice. We can conclude that chronic activation of NF-kB does not have a very damaging effect on transplanted islets. It may be that chronic activation of NF-kB in islets is different than its acute activation, or that NF-kB activities in b cells are less important than previously suggested. Roles of NF-kB in islet transplantation appear to be complex. There is even disagreement about whether NF-kB is activated by the trauma of the isolation process; some find activation while others do not. Given that NF-kB activation does occur, there are questions about how damaging it is because both proapoptotic and antiapoptotic factors can be generated. However, it has been suggested that inhibiting NF-kB prior to and immediately after islet isolation does improve islet transplantation outcome. Nonetheless, there are a variety of death pathways that could be independent of NF-kB such as c-jun NH2-terminal kinases and poly polymerase. In addition, there must be adaptive changes that occur over the time period NF-kB is activated. The acute changes seen after isolation may also be different than those produced through activation by an inducible or Halofuginone cost constitutive transgene. In addition to changes induced by the isolation process, more serious trauma is inflicted during the peritransplant period such as anoxic cell death. Indeed it has been recently suggested that hypoxic conditions can determine whether NF-kB is pro- or anti- apoptotic. A question addressed by this study is 11693460 whether inhibition of NFkB either by genetic or by pharmacological means might protect transplanted islets. In spite of the complexities outlined above, there was reason to think that NF-kB inhibition might protect islets after isolation and/or during the peritransplant period. The bISR mice were created to provide constitutive inhibition of NFkB. Unexpectedly, transplantation of a marginal number of bISR islets did no better than control wild type mouse islets in a syngeneic model. It is entirely possible that an acute intervention might have provided protection not seen with our chronic model, as was reported recently by Rink et al. The current study does however indicate that whatever cell death occurred in this transplant situation was independent of NF-kB. However it should be noted that the situation may be different in the case of allogeneic rejection, where inhibition of NF-kB has been shown to prolong graft survival. Salicylate treatment provided an opportunity to test the effects of pharmacologically interfering with NF-kB. Salicylate is known to inhibit NF-kB and was previously shown to have antiapoptotic effects in human islets. Treatment of recipient mice by addition of salicylate to drinking water provided no benefit, but culture of islets with salicylate prior to transplantation pr