Abstract
Components of the Par-complex, atypical PKC and Par3, have been found to be downregulated upon activation of NF-κB in intestinal epithelial cells. To determine their possible role in pro-inflammatory responses we transduced Caco-2 human colon carcinoma cells with constitutively active (ca) PKCι or anti-Par3 shRNA-expressing lentiviral particles. Contrary to previous reports in other cell types, ca-PKCι did not activate, but rather decreased, baseline NF-κB activity in a luminiscence reporter assay. An identical observation applied to a PB1 domain deletion PKCι, which fails to localize to the tight-junction. Conversely, as expected, the same ca-PKCι activated NF-κB in non-polarized HEK293 cells. Likewise, knockdown of Par3 increased NF-κB activity and, surprisingly, greatly enhanced its response to TNFα, as shown by transcription of IL-8, GRO-1, GRO-2 and GRO-3. We conclude that aPKC and Par3 are inhibitors of the canonical NF-κB activation pathway, although perhaps acting through independent pathways, and may be involved in pro-inflammatory responses.
Highlights
Epithelial apico-basal polarity is controlled by signaling complexes such as the apical aPKC-Par6-Par3 (Par-complex, where atypical PKC comprises PKCf and PKCi/l isoforms)
An identical observation applied to a PB1 domain deletion PKCi, which fails to localize to the tight-junction
It was demonstrated in Caco-2 cells in culture and in an animal model of colitis (Mashukova et al, 2011), as well as a negative correlation of aPKC expression with inflammation in enterocytes from Inflammatory Bowel Disease (IBD) patients (Wald et al, 2011)
Summary
Epithelial apico-basal polarity is controlled by signaling complexes such as the apical aPKC-Par6-Par (Par-complex, where atypical PKC comprises PKCf and PKCi/l isoforms). We found a steep down-regulation of aPKC and Par (Bazooka in Drosophila, not to be confused with Protease Activated Receptors) downstream of a common effector of innate immunity and pro-inflammatory signaling, NF-kB, in human intestinal epithelial cells. It was demonstrated in Caco-2 cells (human colon carcinoma) in culture and in an animal model of colitis (Mashukova et al, 2011), as well as a negative correlation of aPKC expression with inflammation in enterocytes from Inflammatory Bowel Disease (IBD) patients (Wald et al, 2011). To our knowledge, no connection with innate immunity pathways has been described for Par so far
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
