Enhancement of IFN-α and IL-33 production by oral administration of heat-killed K. pneumoniae
Experimental AIP induced by repeated IP injections of poly (I:C) depends on the activation of pDCs, which produce large amounts of IFN-α and IL-33 [14, 16, 19, 20]. Therefore, we examined whether exacerbation of AIP by orally administered K. pneumoniae was associated with the activation of pDCs producing both IFN-α and IL-33. We examined pancreatic immune cell populations by flow cytometry. The percentage of pDCs defined as PDCA-1+B220low cells was significantly higher in MRL/MpJ mice that received orally administered heat-killed K. pneumoniae and IP injections of poly (I:C) than in those treated with the bacterium or IP injections of poly (I:C) alone (Fig. 6A, B). In contrast, the combined treatment with orally administered heat-killed K. pneumoniae and IP injections of poly (I:C) did not change the percentages of CD11b+myeloid cells, CD11c+ DCs, CD3+ T cells, or B220+ B cells, as compared with those following IP injections of poly (I:C) alone (Fig. 6A, B).
Lastly, we determined profiles of proinflammatory cytokine responses in the pancreas. Consistent with marked accumulation of pDCs, co-administration of heat-killed K. pneumoniae and poly (I:C) markedly increased production of IFN-α and IL-33 in the pancreas, as compared with their levels after the administration of heat-killedK. pneumoniae or poly (I:C) alone (Fig. 7). Pancreatic levels of the prototypical innate immunity cytokines IL-6 and TNF-α induced by poly (I:C) injections were similar in the presence and absence of co-administered heat-killed K. pneumonia. We previously showed that pancreatic pDCs producing both IFN-α and IL-33 induce pancreatic expression of adaptive immunity cytokines, including pro-inflammatory IFN-γ and pro-fibrogenic IL-13 [14, 16, 20]. In line with the results of those previous studies, co-administration of heat-killedK. pneumoniae and poly (I:C) enhanced pro-inflammatory and pro-fibrogenic adaptive immune responses because co-administration markedly elevated pancreatic production of IFN-γ and IL-13, as compared with the effect of poly (I:C) administration alone (Fig. 7). Collectively, these data suggest that exacerbation of experimental AIP by oral administration of heat-killed K. pneumoniae was accompanied by pancreatic accumulation of pDCs producing IFN-α and IL-33.