The Attenuation of 14-3-3[zeta] is Involved in the Caffeic Acid-Blocked Lipopolysaccharide-Stimulated Inflammatory Response in RAW264.7 Macrophages

Inflammation plays important roles in the initiation and progress of many diseases. Caffeic acid (CaA) is a naturally occurring hydroxycinnamic acid derivative, which shows hypotoxicity and diverse biological functions, including anti-inflammation. The molecular mechanisms involved in the CaA-inhibited inflammatory response are very complex; generally, the down-regulated phosphorylation of such important transcriptional factors, for example, nuclear factor [kappa]B (NF-[kappa]B) and signal transducers and activators of transcription-3 (STAT-3), plays an important role. Here, we found that in RAW264.7 macrophage cells, CaA blocked lipopolysaccharide (LPS)-stimulated inflammatory response by attenuating the expression of 14-3-3[zeta] (a phosphorylated protein regulator). Briefly, the increased expression of 14-3-3[zeta] was involved in the LPS-induced inflammatory response. CaA blocked the LPS-elevated 14-3-3[zeta] via attenuating the LPS-induced tumor necrosis factor-[alpha] (TNF-[alpha]) secretion and via enhancing the 14-3-3[zeta] ubiquitination. These processes inhibited the LPS-induced activation (phosphorylation) of NF-[kappa]B and STAT-3, in turn blocked the transcriptional activation of inducible NO synthase (iNOS), interleukin-6 (IL-6), and TNF-[alpha], and finally attenuated the productions of nitric oxide (NO), IL-6, and TNF-[alpha]. By understanding a novel mechanism whereby CaA inhibited the 14-3-3[zeta], our study expanded the understanding of the molecular mechanisms involved in the anti-inflammation potential induced by CaA.