Page 4 - ebook

[A. Biochemistry/Molecular Biology] A-2

Acyl chain length of sphingolipid regulates cytokine secretion

via endoplasmic reticulum stress

Su-Jung Kim¹, Min hee Kim¹, Hee-Yeon Kim², Hee-Soo Yoon², Woo-Jae Park¹*, Joo-Won Park²*

¹Department of biochemistry, College of Medicine, Gachon University, Incheon 21999 , Korea, ²Department of

biochemistry, College of Medicine, Ewha Womans University, Seoul 07084, Korea

Distinct acyl chain length of ceramide is detemined by ceramide synthases (CerS). The current study investigated

whether ceramide can have different effects on inflammatory cytokine production and inflammasome formation
depending on its acyl chai length LPS treatment increased CerS6, but reduced CerS2 levels with concomitant

increase of C16-ceramide. While CerS6 overexpression augmented LPS-induced signaling cascades and
inflammasome formation, CerS2 overexpression inhibited it. Since ER stress pathways are known to be involved in

inflammatory cytokine production and inflammasome complex formation, we then examined phosphorylation of
PERK and eIF2A. Phosphorylation of PERK and eIF2A were induced by LPS treatment, which was further intensified

by CerS6 overexpression. However, CerS2 overexpression reduced LPS-induced ER stress response. In addition,
bortezomib, which increases CerS2 and reduces CerS6 protein levels, diminished LPS-induced inflammatory cytokine

production and inflammasome complex formation. Taken together, long chain ceramides produced by CerS6 and
veryl long chain ceramides generated by CerS2 plays an opposite role in LPS-induced inflammation and

inflammsome complex formation by modulating ER stress, MAP kinase and NF-kB signalling pathways.