GSK-3 post-transcriptionally regulates TNF-α biosynthesis in THP-1 macrophages

Few things are more fascinating than finding new interactions between previously unrelated pathways. Glycogen synthase kinase-3 (GSK-3), a ubiquitous kinase initially known for its role in regulating glycogen metabolism, has recently been found to be an indispensable regulator of the TLR4-mediated inflammatory response. GSK-3 inhibition exhibits potent anti-inflammatory effects by acting on both arms of the inflammatory response, reducing the secretion of pro-inflammatory cytokines, and promoting the production of anti-inflammatory cytokines. Tumor Necrosis Factor-α (TNF-α) is among the most important inflammatory cytokines. Aberrant TNF-α expression is associated with various inflammatory conditions, including sepsis and cancer. Thus, understanding the mechanisms regulating TNF-α production could reveal potential therapeutic strategies for TNF-α-associated diseases. Consequently, this study aimed to examine the effect of GSK-3 inhibition on TLR4-induced TNF-a production by THP-1 macrophages. THP-1 macrophages were stimulated with LPS and nigericin in the presence and absence of GSK-3 inhibitor, and TNF-α protein and mRNA levels were evaluated by ELISA and Real-time PCR, respectively. GSK-3 inhibition significantly attenuated TNF-α protein levels in a dose-dependent manner, whereas TNF-α mRNA levels remained unaffected, reflecting a possible post-transcriptional modulation of TNF-α biosynthesis by GSK-3. However, more comprehensive research is needed to elucidate the precise contribution of GSK-3 to TNF-α biosynthesis and to identify novel therapeutic mechanisms to alleviate inflammatory diseases associated with abnormal TNF-α production