SK-126, a synthetic compound, regulates the production of inflammatory cytokines induced by LPS in antigen-presenting cells

A variety of mediators released by immune cells triggers or enhances specific aspects of the inflammatory response. Dendritic cells (DCs) play an essential role in the innate immune system by shaping the adaptive immune responses and by controlling the production of cytokines in response to inflammatory stimuli. In the present study, we investigated whether SK-126, a pyridine derivative based on gentianine originated from a natural product, can affect the LPS-induced inflammatory cytokine production in DC. Interestingly, treatment of mouse bone marrow-derived dendritic cells (BMDCs) and the murine dendritic cell line, DC 2.4, with SK-126 completely suppressed LPS-induced TNF-alpha expression at both transcriptional and protein levels. In contrast to TNF-alpha, SK-126 enhanced IL-10 expression at both transcriptional and protein levels. To determine signaling pathways involved in the regulation of inflammatory cytokines, we examined the involvement of MAPK and the transcription factor, NF-kappa B. SK-126 enhanced ERK1/2 and p38 activation following LPS stimulation, but it did not induce phosphorylation of SAPK/JNK and NF-kappa B. Also, STAT3 phosphorylation after LPS stimulation was increased by SK-126 to a large extent. Using specific inhibitors, we confirmed that SK-126 has dual effects in which it suppresses TNF-alpha production and enhances IL-10 production via the up-regulation of ERK1/2 and p38. Finally, LPS-induced inflammatory responses such as TNF-alpha. production in vivo were significantly reduced by treatment with SK-126. Therefore, our findings suggest that SK-126 may be a useful drug candidate to treat inflammatory diseases in which pro- or anti-inflammatory cytokines play a significant role in their pathogenesis. (c) 2007 Elsevier Inc. All rights reserved.