PKR in DSS-induced Colitis

To the Editor: The double-stranded RNA (dsRNA)-activated protein kinase (PKR) is a fundamental signaling pathway in the host antiviral interferon response. Studies reported by Rath et al using mice with deletion of the C-terminal catalytic kinase domain of PKR1 suggest that PKR is detrimental to the host in the context of injury that results in colonic inflammation.2 These findings conflict with our results that show Pkr−/− mice with deletion of the N-terminal dsRNA binding domain3 display impaired survival of intestinal epithelial cells and greater intestinal inflammation in an experimental model of colitis.4 In general, we concur with the sentiments of Rath et al regarding the potential differences between the N-terminal and C-terminal murine deletion mutants of PKR. However, the level of expression of the N-terminal truncated PKR kinase domain is extremely low.5 In addition, the studies of Cao et al detected reduced eIF2α phosphorylation in the Pkr-null mice and this was not increased upon dextran sodium sulfate (DSS) treatment. The findings indicate that induction of the endogenous truncated allele does not contribute to eIF2α phosphorylation in this model. Importantly, another factor that contributes to DSS sensitivity is the genetic background.6,7 Although both Cao et al and Rath et al used mixed backgrounds for the Pkr-deleted mice (Cao et al used a 129Sv(ev)/C57BL/6 background and Rath et al used a 129/ terSv/BALB/C background), Cao et al used littermate controls to rule out effects of genetic background and maternal host microflora. In contrast, Rath et al used inbred BALB/C mice as controls. Numerous reports demonstrate that genetic background as well as maternal microflora significantly impact progression of intestinal inflammation in animal models.6,–10 Therefore, it is important to consider the impact of genetic background and maternal microflora contributions in these inflammatory responses. In addition, Cao et al used bone marrow chimeras for the DSS colitis experiments to study effects in intestinal epithelial cells, while Rath et al used whole-body C-terminal deleted Pkr. Although many cellular pathways are intact in cells expressing C-terminal deleted PKR,1,5 some signal transduction pathways including phosphoinositide 3-kinase (PI3K) signaling are impaired in the absence of the C-terminal catalytic domain.11 Given the important role of the PI3K family in immunity,12 it is possible that the protective effect of the C-terminal deletion in PKR during DSS colitis is partially due to a reduced inflammatory response from the immune cells. Certainly, the studies warrant further investigation.