Vaticanol B, a resveratrol tetramer, regulates endoplasmic reticulum stress and inflammation

Abstract

Enhanced endoplasmic reticulum (ER) stress has been implicated in various pathological situations including inflammation. During a search for compounds that regulate ER stress, we identified vaticanol B, a tetramer of resveratrol, as an agent that protects against ER stress-induced cell death. Vaticanol B suppressed the induction of unfolded protein response-targeted genes such as glucose-regulated protein 78 (GRP78) and C/EBP-homologous protein (CHOP) after cells were treated with ER stressors. Analysis in the mouse macrophage cell line RAW 264.7 revealed that vaticanol B also possesses a strong anti-inflammatory activity. Production of a variety of inflammatory modulators such as tumor necrosis factor-alpha, nitric oxide, and prostaglandin E(2) was inhibited by vaticanol B to a much greater extent than by monomeric or dimeric resveratrol after exposure of cells to lipopolysaccharide. Further investigations to determine the common mechanisms underlying the regulation of ER stress and inflammation by vaticanol B disclosed an important role for vaticanol B in regulation of basic gene expression and in prevention of the protein leakage from the ER into the cytosol in both conditions. These results suggest that vaticanol B is a novel anti-inflammatory agent that improves the ER environment by reducing the protein load on the ER and by maintaining the membrane integrity of the ER.

Endoplasmic Reticulum Stress–Induced IRE1α Activation Mediates Cross-Talk of GSK-3β and XBP-1 To Regulate Inflammatory Cytokine Production

“…1A, ER stress induced the upregulation of IL-1b and TNF-a gene expression in a manner similar to LPS, indicating that an ER stress-induced downstream event can regulate the expression of proinflammatory cytokines. Consistent with previous reports (19), the expression of CHOP, a classic ER stress response, was induced by TM treatment, but not by LPS treatment (Supplemental Fig. 1A).…”

“…ER stress-induced GSK-3b activation differently regulates IL-1b and TNF-a mRNA expression in cultured macrophages ER stress-mediated UPRs have been suggested to be involved in the activation of NF-kB, which regulates genes encoding proinflammatory cytokines such as IL-1b, TNF-a, and IL-6 (18)(19)(20)(21)(22). Moreover, activation of NF-kB and expression of the proinflammatory cytokines have been observed in the liver of mice challenged with the pharmacologic ER stress inducer TM (23).…”

“…In fact, all three arms of the UPR have been suggested to be involved in the activation of NF-kB, which regulates genes encoding proinflammatory cytokines such as IL-1b, TNF-a, and IL-6 (16,18,19). For instance, IRE1a together with TNFRassociated factor 2 binds to and activates I-kB kinase, which induces I-kB degradation, thereby leading to NF-kB activation (20)(21)(22).…”

Endoplasmic Reticulum Stress Induced by Surfactant Protein C BRICHOS Mutants Promotes Proinflammatory Signaling by Epithelial Cells

“…A number of studies showed that, in addition to 4-PBA, treatment with small molecule chaperones can restore proper protein folding and ER function. These chaperones include taurine-conjugated ursodeoxycholic acid, vaticanol B, and others, which were shown to decrease aggregate formation and prevent an ER stress response (48,49). Although these treatments have shown promising results, they will likely have to be simultaneously evaluated for offtarget effects on the many other cellular pathways that link ER stress and cellular dysfunction.…”

Efficacy of Dibenzoylmethane Derivatives in Protecting against Endoplasmic Reticulum Stress and Inhibiting Nuclear Factor Kappa B on Dextran Sulfate Sodium Induced Colitis in Mice

“…In addition, Kaser et al 7) reported that the transcription factor X-box binding protein 1 (XBP1), which is an important key to ER stress response, is involved in the genetic risk of onset of IBD in humans. These findings suggest a possible correlation between IBD and ER stress.We reported that dantrolene, an antagonist of ryanodine receptors in the ER, and some antioxidants such as a-tocopherol, partly prevented tunicamycin-induced cell death in F9 homocystein-induced ER protein null cells.8) Using this cell line, our group and others have reported that 103 plantderived compounds 9,10) and 200 synthetic compounds including dibenzoylmethane (DBM) derivatives, 11) carbazole derivatives, 12) and pyrimidine derivatives were screened previously, and some DBM derivatives improved cell viability after tunicamycin treatment at a level similar to that achieved by dantrolene in F9 Herp null cells.11) However, it remains unclear whether DBM derivatives that have protective effects against ER stress are effective against colitis.Nuclear factor kB (NF-kB) is a dimeric transcription factor that induces the expression of genes involved in the inflammatory process. Activation of NF-kB has been observed in the mucosa of patients with ulcerative colitis, 13) and butyrate has been shown to inhibit NF-kB activation in lamina propia macrophages of patients with ulcerative colitis.…”