Effects of a novel microtubule-depolymerizer on pro-inflammatory signaling in RAW264.7 macrophages.

ABSTRACT: The Nuclear Factor-kappa B (NF-?B) pathway is vital for immune system regulation and pro-inflammatory signaling. Many inflammatory disorders and diseases, including cancer, are linked to dysregulation of NF-?B signaling. When macrophages recognize the presence of a pathogen, the signaling pathway is activated, resulting in the nuclear translocation of the transcription factor, NF-?B, to turn on pro-inflammatory genes. Here, we demonstrate the effects of a novel microtubule depolymerizer, NT-07-16, a polysubstituted pyrrole compound, on this process. Treatment with NT-07-16 decreased the production of pro-inflammatory cytokines in RAW264.7 mouse macrophages. It appears that the reduction in pro-inflammatory mediators produced by the macrophages after exposure to NT-07-16 may be due to activities upstream of the translocation of NF-?B into the nucleus. NF-?B translocation occurs after its inhibitory protein, I?B-? is phosphorylated which signals for its degradation releasing NF-?B so it is free to move into the nucleus. Previous studies from other laboratories indicate that these processes are associated with the microtubule network. Our results show that exposure to the microtubule-depolymerizer, NT-07-16 reduces the phosphorylation of I?B-? and also decreases the association of NF-?B with tubulin which may affect the ability of NF-?B to translocate into the nucleus. Therefore, the anti-inflammatory activity of NT-07-16 may be explained, at least in part, by alterations in these steps in the NF-?B signaling pathway leading to less NF-?B entering the nucleus and reducing the production of pro-inflammatory mediators by the activated macrophages.

SUBMITTER: Gilmore SP 

PROVIDER: S-EPMC5766364 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature