Abstract
Cucurbitacin IIb (CuIIb) is one of the major active compounds in Hemsleyadine tablets which have been used for clinical treatment of bacillary dysentery, enteritis and acute tonsilitis. However, its action mechanism has not been completely understood. This study aimed to explore the anti-inflammatory activity of CuIIb and its underlying mechanism in mitogen-activated lymphocytes isolated from mouse mesenteric lymph nodes. The results showed that CuIIb inhibited the proliferation of concanavalin A (Con A)-activated lymphocytes in a time- and dose-dependent manner. CuIIb treatment arrested their cell cycle in S and G2/M phases probably due to the disruption of the actin cytoskeleton and the modulation of p27Kip1 and cyclin levels. Moreover, the surface expression of activation markers CD69 and CD25 on Con A-activated CD3+ T lymphocytes was suppressed by CuIIb treatment. Both Con A- and phorbol ester plus ionomycin-induced expression of TNF-α, IFN-γ and IL-6 proteins was attenuated upon exposure to CuIIb. Mechanistically, CuIIb treatment suppressed the phosphorylation of JNK and Erk1/2 but not p38 in Con A-activated lymphocytes. Although CuIIb unexpectedly enhanced the phosphorylation of IκB and NF-κB (p65), it blocked the nuclear translocation of NF-κB (p65). In support of this, CuIIb significantly decreased the mRNA levels of IκBα and TNF-α, two target genes of NF-κB, in Con A-activated lymphocytes. In addition, CuIIb downregulated Con A-induced STAT3 phosphorylation and increased cell apoptosis. Collectively, these results suggest that CuIIb exhibits its anti-inflammatory activity through modulating multiple cellular behaviors and signaling pathways, leading to the suppression of the adaptive immune response.
Highlights
Cucurbitacins belong to a large family of triterpenoid compounds found in Cucurbitaceae plants and they possess a wide spectrum of biological and pharmacological activities [1,2,3,4,5]
We used these unsorted lymphocytes stimulated with concanavalin A (Con A) as a model of in vitro lymphocyte responses, which may mimic the in vivo system to some extent
The results showed that cucurbitacin IIa and IIb (CuIIb) of less than 11 mM had minimal cytotoxicity on the lymphocytes after 4-h treatment (Figure 1B)
Summary
Cucurbitacins belong to a large family of triterpenoid compounds found in Cucurbitaceae plants and they possess a wide spectrum of biological and pharmacological activities [1,2,3,4,5]. The root of Hemsleya amabilis contains two closely related cucurbitacins: cucurbitacin IIa and IIb (CuIIb); Hemsleyadine tablets made of Hemsleya amabilis root extract, which contain both cucurbitacin IIa and IIb, have been shown effective for bacillary dysentery, enteritis and acute tonsillitis [7] These clinical observations suggest that cucurbitacin IIa and IIb have anti-inflammatory properties. A naıve T lymphocyte activates several critical signaling pathways, such as the mitogen-activate protein kinases (MAPKs) and NF-kB pathways [11,12] and undergoes profoundly changes including activation, proliferation, and cytokine expression, leading to a robust clonal expansion All these processes may be pharmacologically manipulated, representing important targets for therapeutic invention against inflammatory diseases [13]. It is of interest to explore the effects of CuIIb on the cellular behaviors of lymphocytes in response to mitogenic stimulation
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