7-Hydroxy Frullanolide, a sesquiterpene lactone, increases intracellular calcium amounts, lowers CD4+ T cell and macrophage responses, and ameliorates DSS-induced colitis

Pathak, S and Gokhroo, A and Kumar Dubey, A and Majumdar, S and Gupta, S and Almeida, A and Mahajan, GB and Kate, A and Mishra, P and Sharma, R and Kumar, S and Vishwakarma, R and Balakrishnan, A and Atreya, H and Nandi, D (2021) 7-Hydroxy Frullanolide, a sesquiterpene lactone, increases intracellular calcium amounts, lowers CD4+ T cell and macrophage responses, and ameliorates DSS-induced colitis. In: International Immunopharmacology, 97 .

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Abstract

Sesquiterpene lactones are a class of anti-inflammatory molecules obtained from plants belonging to the Asteraceae family. In this study, the effects of 7-hydroxy frullanolide (7HF), a sesquiterpene lactone, in inhibiting CD4+ T cell and peritoneal macrophage responses were investigated. 7HF, in a dose dependent manner, lowers CD69 upregulation, IL2 production and CD4+ T cell cycling upon activation with the combination of anti-CD3 and anti-CD28. Further mechanistic studies demonstrated that 7HF, at early time points, increases intracellular Ca2+ amounts, over and above the levels induced upon activation. The functional relevance of 7HF-induced Ca2+ increase was confirmed using sub-optimal amounts of BAPTA, an intracellular Ca2+ chelator, which lowers lactate and rescues CD4+ T cell cycling. In addition, 7HF lowers T cell cycling with the combination of PMA and Ionomycin. However, 7HF increases CD4+ T cell cycling with sub-optimal activating signals: only PMA or anti-CD3. Furthermore, LPS-induced nitrite and IL6 production by peritoneal macrophages is inhibited by 7HF in a Ca2+-dependent manner. Studies with Ca2+ channel inhibitors, Ruthenium Red and 2-Aminoethoxydiphenyl borate, lowers the inhibitory effects of 7HF on CD4+ T cell and macrophage responses. In silico studies demonstrated that 7HF binds to Ca2+ channels, TRPV1, IP3R and SERCA, which is mechanistically important. Finally, intraperitoneal administration of 7HF lowers serum inflammatory cytokines, IFNγ and IL6, and reduces the effects of DSS-induced colitis with respect to colon length and colon damage. Overall, this study sheds mechanistic light on the anti-inflammatory potential of 7HF, a natural plant compound, in lowering immune responses. © 2021 Elsevier B.V.

Item Type:	Journal Article
Publication:	International Immunopharmacology
Publisher:	Elsevier B.V.
Additional Information:	The copyright for this article belongs to Elsevier B.V.
Department/Centre:	Division of Biological Sciences > Biochemistry Division of Chemical Sciences > NMR Research Centre (Formerly Sophisticated Instruments Facility) UG Programme
Date Deposited:	10 Aug 2021 10:26
Last Modified:	10 Aug 2021 10:26
URI:	http://eprints.iisc.ac.in/id/eprint/69088

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