This was similarly seen in P. aeruginosa-infected cav1 KO mice [[9]]. Interestingly, IL-6 was also elevated not only in cav1 KO mice challenged with K. pneumoniae, but also in those exposed to P. aeruginosa. IL-6 plays disparate roles in inflammatory responses during bacterial infections [[25]]. IL-6 protects the host from death following K. pneumoniae infection; however, IL-6 neutralizing antibodies improve survival in
polymicrobial septic peritonitis [[26]]. Since IL-17R-deficient mice were shown to be more susceptible to Selleckchem Stem Cell Compound Library K. pneumonia infection [[27]], we measured IL-17 levels and found an increase in cav1 KO mice compared with WT mice lungs. In fact, the susceptibility of IL-17-deficient mice to K. pneumoniae has been directly associated with delayed neutrophil recruitment and reduced G-CSF [[28]]. IL-17 has also been documented to induce secretion
of TNFα, IL-1β, and IL-6 [[29]]. The proinflammatory response to K. pneumoniae may not improve survival rates, but it aggravates existing disease conditions as shown in cav1 KO mice infected with P. aeruginosa [[9, 11]]. Despite the elevated levels of TNF-α, IL-1β, IL-6, and IL-17 in BAL fluid, the overall survival of cav1 KO mice with K. pneumoniae infection deteriorated rapidly. Interestingly, IL-27p28, a novel cytokine, was also increased in infected cav1 KO mice. p28, a subunit of IL-27, has broad inhibitory effects on Th1, Th2, and Th17 subsets
as well as the expansion of regulatory T cells [[30]]. Hence, we selleck products Amisulpride propose that the elevated IL-27 may provide a passive regulatory mechanism during acute infection. Given that MIP2 is a chemokine primarily produced by macrophages, our finding that MIP2 levels were not elevated in the lung indicates an impaired alveolar macrophage population. This in turn suggests that distinct compartmental immunity occurs in K. pneumoniae infection [[31]]. In addition, the phagocytic ability of AMs was found to be downregulated in K. pneumoniae-infected cav1 KO mice (data not shown). It has been suggested that Cav1 is an immune-modulatory effector on cytokine production through the MKK3/p38 MAPK pathway [[32]]. We found that ERK1/2 was activated in cav1 KO mice. We also noted a decreased TLR-4 response that was previously linked to gram-negative bacteria, suggesting a troublesome lack of innate immunity in cav1 KO mice. We also observed that GSK3β−β-catenin−Akt pathway may be involved in this infection, with both Akt and β-catenin being downregulated by Cav1 deficiency. By contrast, GSK3β expression and phosphorylation are significantly increased following loss of Cav1. This is consistent with the previous studies that show that GSK3β can destabilize β-catenin [[17]]. Although Akt is usually an upstream signal for GSK3β [[33, 34]], in this case the Akt changes may result from the effects of GSK3β [[35]].