Anti-inflammatory effects of 1, 9-Diallyl-9H-pyrido[3, 4-b]indole in activated human neutrophils through inhibiting Src family kinases

[Speaker] Hsiang-chih Ku:1
[Co-author] Tsong-Long Hwang:1
1:Graduate Institute of Natural Products, Chang Gung University, Taiwan

Neutrophils play an important role in innate immunity. However, recent evidences have suggested that neutrophils are involved in the pathogenesis of various inflammatory and autoimmune diseases. Therefore, suppression of neutrophil activation using drug has therapeutic potential in neutrophil-mediated diseases. In this study, we demonstrated that 1,9-Diallyl-9H-pyrido[3,4-b]indole (NCKU-S-4) significantly inhibited various stimulators-induced human neutrophil activations, including superoxide anion generation, reactive oxygen species, elastase release, CD11b expression, chemotactic migration, and neutrophil extracellular traps (NETs) formation. NCKU-S-4 did not directly scavenge superoxide anion and cause cytotoxicity. NCKU-S-4 significantly inhibited the phosphorylation of the Src family kinases (SFKs), Src (Tyr416), Lyn (Tyr396), HCK (Tyr410), but not p38 MAPK (Thr180/Tyr182), ERK (Thr202/Tyr204), and JNK (Thr183/Tyr185). Further study showed that NCKU-S-4 directly inhibited the enzymatic activities of Src and Fgr, suggesting that NCKU-S-4 acts as an inhibitor of SFKs. In addition, the downstream signals of SFKs, Vav (Tyr174) and Btk (Tyr223), were inhibited by NCKU-S-4. In conclusion, these data demonstrated that NCKU-S-4 inhibits oxidative burst, degranulation, migration and NETosis in activated human neutrophils through inhibition of SFKs activity. We suggest that NCKU-S-4 may has potential as an anti-inflammatory agent for treating neutrophilic inflammation.
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