Protective effect of gedunin on TLR-mediated inflammation by modulation of inflammasome activation and cytokine production: Evidence of a multitarget compound

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• 作者：Perla Villani Borges^a ; Katelim Hottz Moret^a ; Nulgumnalli Manjunathaiah Raghavendra^b ; ^c ; Thadeu Estevam Maramaldo Costa^a ; ^c ; Ana Paula Monteiro^d ; Alan Brito Carneiro^d ; Patrí ; cia Pacheco^a ; ¹ ; Jairo Ramos Temerozo^e ; Dumith Chequer Bou-Habib^e ; Maria das Graç ; as Henriques^a ; ^c ; Carmen Penido^a ; ^c ; ^{cpenido@cdts.fiocruz.br}
• 关键词：ASC ; apoptosis-associated speck-like protein containing caspase activation and recruitment domain ; ATP ; adenosine triphosphate ; CARD ; caspase activation and recruitment domain ; DMEM ; dulbecco's modified eagle medium ; DMSO ; dimethyl sulfoxide ; HO-1 ; heme oxigenase-1 ; Hsp ; heat shock protein ; IL ; interleukin ; i.pl. ; intrapleural ; LPS ; lipopolysaccharide ; MD-2 ; myeloid differentiation protein-2 ; NLRP3 ; nucleotide-binding domain and leucine-rich repeat protein-3 ; NO ; nitric oxide ; PAM3 ; palmitoyl-3-
• 刊名：Pharmacological Research
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：115
• 期：Complete
• 页码：65-77
• 全文大小：2974 K
• 卷排序：115

文摘

Activation of toll-like receptors (TLRs) by pathogen-associated molecular patterns (PAMPs) triggers an innate immune response, via cytokine production and inflammasome activation. Herein, we have investigated the modulatory effect of the natural limonoid gedunin on TLR activation in vitro and in vivo. Intraperitoneal (i.p.) pre- and post-treatments of C57BL/6 mouse with gedunin impaired the influx of mononuclear cells, eosinophils and neutrophils, as well as the production of tumor necrosis factor (TNF)-α, interleukin (IL)-6 and nitric oxide (NO), triggered by lipopolysaccharide (LPS) in mouse pleura. Accordingly, in vitro post-treatment of immortalized murine macrophages with gedunin also impaired LPS-induced production of such mediators. Gedunin diminished LPS-induced expression of the nucleotide-binding domain and leucine-rich repeat protein-3 (NLRP3) on pleural leukocytes in vivo and in immortalized macrophages in vitro. In line with this, gedunin inhibited LPS-induced caspase-1 activation and the production of IL-1β in vivo and in vitro. In addition, gedunin treatment triggered the generation of the anti-inflammatory factors IL-10 and heme oxigenase-1 (HO-1) at resting conditions or upon stimulation. We also demonstrate that gedunin effect is not restricted to TLR4-mediated response, since this compound diminished TNF-α, IL-6, NO, NLRP3 and IL-1β, as well as enhanced IL-10 and HO-1, by macrophages stimulated with the TLR2 and TLR3 agonists, palmitoyl-3-Cys-Ser-(Lys)4 (PAM3) and polyriboinosinic:polyribocytidylic acid (POLY I:C), in vitro. In silico modeling studies revealed that gedunin efficiently docked into caspase-1, TLR2, TLR3 and to the myeloid differentiation protein-2 (MD-2) component of TLR4. Overall, our data demonstrate that gedunin modulates TLR4, TLR3 and TLR2-mediated responses and reveal new molecular targets for this compound.