St. John's wort extract and hyperforin inhibit multiple phosphorylation steps of cytokine signaling and prevent inflammatory and apoptotic gene induction in pancreatic β cells. (December 2016)

• Record Type: Journal Article
• Authors: Novelli, Michela; Menegazzi, Marta; Beffy, Pascale; Porozov, Svetlana; Gregorelli, Alex; Giacopelli, Daniela; De Tata, Vincenzo; Masiello, Pellegrino
• Is Part Of: International journal of biochemistry & cell biology. Volume 81:Part A(2016:Dec.)
• Page Start: 92
• Page End: 104
• Publication Date: 2016-12
• Subjects: BAD BCL2-associated agonist of cell death -- BIM BCL2-like 11 -- CHOP C/EBP homologous protein -- CIITA Class II major histocompatibility complex transactivator -- COX2 Cyclo-oxygenase 2 -- DP5 Death protein 5 -- EMSA Electrophoretic mobility shift assay -- ER Endoplasmic reticulum -- ERK Extracellular signal-regulated kinase -- FOXO1 Forkhead box O1 -- HPF Hyperforin -- ICAM1 Intercellular adhesion molecule 1 -- IFN-γ Interferon gamma -- IκB Inhibitor of kappa-B -- IKK NF-kappaB inhibitory subunit IkappaB kinase -- iNOS Inducible NO synthetase -- IL-1β Interleukin-1 beta -- JNK c-Jun N-terminal kinase -- MAPK Mitogen-activated protein kinase -- NF-κB Nuclear factor kappa-B -- PDX1 Pancreatic duodenal homeobox 1 -- PUMA p53 upregulated modulator of apoptosis -- SJW St. John's wort -- STAT-1 Signal transducer and activator of transcription 1 -- TNF-α Tumor necrosis factor alpha; Pancreatic beta cells -- Cytokines -- Signaling pathways -- Cell death -- Type 1 diabetes -- Natural compounds; Biochemistry -- Periodicals; Cytology -- Periodicals; Biochemistry -- Periodicals; Cell Biology -- Periodicals; Biochimie -- Périodiques; Cytologie -- Périodiques; Biochimie; Cytologie; Biochemistry; Cytology; Ressource Internet (Descripteur de forme); Périodique électronique (Descripteur de forme); Periodicals; 572.05
• DOI: 10.1016/j.biocel.2016.10.017
• Languages: English
• ISSNs: 1357-2725

Abstract

Graphical abstract: Highlights: St. John's wort extract (SJW) and hyperforin (HPF) block cytokine effects in β cells. SJW and HPF simultaneously inhibit cytokine-induced STAT-1, NF-κB and MAPK activation. SJW and HPF hinder multiple phosphorylation steps of signaling pathways. SJW and HPF prevent induction of inflammatory and apoptotic cytokine target genes. These natural compounds are exploitable for prevention of immune-mediated β-cell loss. Abstract: The extract of the herbaceous plant St. John's wort (SJW) and its phloroglucinol component hyperforin (HPF) were previously shown to inhibit cytokine-induced STAT-1 and NF-κB activation and prevent damage in pancreatic β cells. To further clarify the mechanisms underlying their protective effects, we evaluated the phosphorylation state of various factors of cytokine signaling pathways and the expression of target genes involved in β-cell function, inflammatory response and apoptosis induction. In the INS-1E β-cell line, exposed to a cytokine mixture with/without SJW extract (2–5 μg/ml) or HPF (1–5 μM), protein phosphorylation was assessed by western blotting and expression of target genes by real-time quantitative PCR. SJW and HPF markedly inhibited, in a dose-dependent manner (from 60 to 100%), cytokine-induced activating phosphorylations of STAT-1, NF-κB p65 subunit and IKK (NF-κB inhibitory subunit IκBα kinase). MAPK and Akt pathways were also modulated by the vegetal compounds through hindrance of p38 MAPK, ERK1/2, JNK and Akt phosphorylations, each reduced by at least 65% up to 100% at the higher dose. Consistently, SJW and HPF a) abolished cytokine-induced mRNA expression of pro-inflammatory genes; b) avoided down-regulation of relevant β-cell functional/differentiation genes; c) corrected cytokine-driven imbalance between pro- and anti-apoptotic factors, by fully preventing up-regulation of pro-apoptotic genes and preserving expression or function of anti-apoptotic Bcl-2 family members; d) protected INS-1E cells against cytokine-induced apoptosis. In conclusion, SJW extract and HPF exert their protective effects through simultaneous inhibition of multiple phosphorylation steps along various cytokine signaling pathways and consequent restriction of inflammatory and apoptotic gene expression. Thus, they have a promising therapeutic potential for the prevention or limitation of immune-mediated β-cell dysfunction and damage leading to type 1 diabetes.