Furthermore, the results from our in vitro model are in agreement with findings generated in a macaque model of SHIV infection. Vaginal levels of IL 6, IL 8, IL 1B and IL 1RA were not different between macaques with no lactobacilli, those colonized with lactobacillus indigenous for the macaque and those colonized with mCV N expressing L. jensenii 1153 1666. Other commensal bacteria have selleck chemicals Crizotinib also been shown to downregulate Inhibitors,Modulators,Libraries inflammatory responses. For ex ample, H. pylori downregulated IL 8, MIP 3 and other chemokines through inducing microRNA expression in host epithelial cells. Further research is required to determine the molecular mechanisms, by which vaginal L. jensenii, L. crispatus and L. acidohilus tune the host innate immune responses to avoid proinflammatory protein pro duction in the presence of a potent NFB activation.
The innate immunity mediators assessed here are known as indicators of mucosal toxicity, and inflammation and have been used and recom mended for microbicide safety evaluation. In contrast to IL 1RA, which displays anti inflammatory properties , the pro inflammatory cytokines IL 1, TNF, IL 6 and Inhibitors,Modulators,Libraries IL 8 can activate HIV viral repli cation Inhibitors,Modulators,Libraries in infected cells. Similarly vaginal inflam mation increases the risk of HIV transmission by increasing the number of host cells at the site of infec tion. IL 8 is also involved in the recruitment of innate immune cells, neutrophils and CD4 positive T cells to the site of infection. MIP 3 is a chemokine recruiting dendritic cells and along with RANTES, a chemokine for T cells, is known to play a role in the early recruitment of HIV target cells.
Thus, the lack of upregulation of these proinflammatory mediators by the cervicovaginal epithelial cells is a desired safety feature of the mCV N expressing L. jensenii strain. Concerns about the safety of CV N in the absence of lactobacillus have been raised by Huskens Inhibitors,Modulators,Libraries et al. showing that administration of CV N to pre stimulated PBMC induced proinflammatory cytokine upregulation and it also had in vitro mitogenic activity. It is important to clarify that the study by Huskens et al. is of limited rele vance to the clinical application of the mCV N expressing lactobacilli for several reasons 1 the mCV N is a genetic ally modified stable monomeric derivative of the natural cyanobacterium produced CV N protein referred to in that older study, 2 Huskens et al.
seemed to have used E. coli expressed CV N protein. however, they dont ad dress steps taken to eliminate or control for endotoxin contamination in their experiments. In contrast, in our study mCV N Inhibitors,Modulators,Libraries is expressed in the context of lactobacillus which lacks endotoxin. IL 1, IL 1RA and SLPI are stored in the epithelial cell and enzyme inhibitor released upon membrane damage. The fact that none of the L. jensenii strains caused significant increase in these mediators suggests preserved mem brane integrity in addition to lack of immunotoxicity.