HSP90 Inhibition Suppresses PGE2 Production via Modulating COX-2 and 15-PGDH Expression in HT-29 Colorectal Cancer Cells

Jiang

et al. 2016

IJMS

Chloranthalactone B (CTB), a lindenane-type sesquiterpenoid, was obtained from the Chinese medicinal herb Sarcandra glabra, which is frequently used as a remedy for inflammatory diseases. However, the anti-inflammatory mechanisms of CTB have not been fully elucidated. In this study, we investigated the molecular mechanisms underlying these effects in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. CTB strongly inhibited the production of nitric oxide and pro-inflammatory mediators such as prostaglandin E2, tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β), and IL-6 in RAW264.7 cells stimulated with LPS. A reverse-transcription polymerase chain reaction assay and Western blot further confirmed that CTB inhibited the expression of inducible nitric oxide synthase, cyclooxygenase-2, TNF-α, and IL-1β at the transcriptional level, and decreased the luciferase activities of activator protein (AP)-1 reporter promoters. These data suggest that inhibition occurred at the transcriptional level. In addition, CTB blocked the activation of p38 mitogen-activated protein kinase (MAPK) but not c-Jun N-terminal kinase or extracellular signal-regulated kinase 1/2. Furthermore, CTB suppressed the phosphorylation of MKK3/6 by targeting the binding sites via formation of hydrogen bonds. Our findings clearly show that CTB inhibits the production of inflammatory mediators by inhibiting the AP-1 and p38 MAPK pathways. Therefore, CTB could potentially be used as an anti-inflammatory agent.

Section: Resultsmentioning

confidence: 99%

Anti-Inflammatory Effects of Chloranthalactone B in LPS-Stimulated RAW264.7 Cells

Jiang

et al. 2016

IJMS

Journal of Biological Chemistry

“…There are a few studies that have examined a relationship between Cox-2 and HSP27 during myofibroblast migration (42,43). Additionally, a recent study reported that HSP90 inhibition decreased Cox-2 mRNA expression and protein level in a colorectal cancer cell line (44). In light of the fact that IL-4 treatment of macrophages increases the expression of these chaperones, whereas significantly down-regulating Cox-2 protein and increasing Cox-1 protein, it is plausible that Cox-1 interacts with HSPs, due to high structural similarities between Cox-1 and Cox-2, leading to the stabilization of Cox-1 protein.…”

Section: Discussionmentioning

confidence: 99%

IL-4 up-regulates cyclooxygenase-1 expression in macrophages

Shay

Diwakar

Guan

et al. 2017

Macrophages use various cell-surface receptors to sense their environment and undergo polarized responses. The cytokines, interleukin (IL)-4 and IL-13, released from T-helper type 2 (Th2) cells, drive macrophage polarization toward an alternatively activated phenotype (M2). This phenotype is associated with the expression of potent pro-resolving mediators, such as the prostaglandin (PG) D 2-derived cyclopentenone metabolite, 15d-PGJ 2 , produced by the cyclooxygenase (Ptgs; Cox) pathway. Interestingly, IL-4 treatment of bone marrow-derived macrophages (BMDMs) significantly down-regulates Cox-2 protein expression, whereas Cox-1 levels are significantly increased. This phenomenon not only challenges the dogma that Cox-1 is only developmentally regulated, but also demonstrates a novel mechanism in which IL-4-dependent regulation of Cox-1 involves the activation of the mechanistic target of rapamycin complex (mTORC). Using specific chemical inhibitors, we demonstrate here that IL-4-dependent Cox-1 up-regulation occurs at the post-transcriptional level via the Fes-Akt-mTORC axis. Activation of AMP-activated protein kinase (AMPK) by metformin, inhibition of mTORC by torin 1, or CRISPR/Cas9-mediated genetic knockout of tuberous sclerosis complex-2 (Tsc2) blocked the IL-4-dependent expression of Cox-1 and the ability of macrophages to polarize to M2. However, use of 15d-PGJ 2 partially rescued the effects of AMPK activation, suggesting the importance of Cox-1 in macrophage polarization as also observed in a model of gastrointestinal helminth clearance. In summary, these findings suggest a new paradigm where IL-4-dependent up-regulation of Cox-1 expression may play a key role in tissue homeostasis and wound healing during Th2-mediated immune responses, such as parasitic infections.

“…Furthermore, urinary high levels of PGE2 were also was found in lupus nephritis which was the result of increased activity of COX‐2 . PGE2 level was regulated by both synthetic (COX‐2 enzyme) and catabolic (15‐PGDH enzyme) pathways . Human lupus T cells have high levels of COX‐2 expression that help them escape from apoptosis; therefore it is proposed that inhibition of COX‐2 may be a therapeutic strategy for SLE treatment via induction of apoptosis in lupus autoreactive immune cells .…”

Section: Discussionmentioning

confidence: 99%

“…PGE2 is a major product of the COX pathway. The PGE2 level is controlled by a balance between its synthesis mediator (COX‐2 enzyme) and its catabolic key enzyme (15‐hydroxyprostaglandin dehydrogenase [15‐PGDH] enzyme) . PGE2 regulates the activation of mature B lymphocytes via overproduction of immunoglobulin (Ig)E and IgG .…”

Section: Introductionmentioning

confidence: 99%

Association between COX‐2 and 15‐PGDH polymorphisms and SLE susceptibility

et al. 2020

Int J Rheum Dis. 2020;23:627-632. | 627 wileyonlinelibrary.com/journal/apl | INTRODUC TI ONSystemic lupus erythematosus (SLE) is a heterogeneous and chronic inflammatory autoimmune disease which has important features, such as autoantibody production against host nuclear antigens and multi-organ inflammation (like skin, kidneys, and brain). 1,2 Its occurrence is more common in women than men. 3 SLE etiology is unknown. Environmental factors, such as UV radiation, AbstractAims: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease. Prostaglandins E2 (PGE2), the product of the cyclo-oxygenase 2 (COX-2) enzyme, has critical roles in the etiology of autoimmune diseases. PGE2 level is controlled by a balance between its synthesis mediator (COX-2 enzyme) and its catabolic key enzyme (15-hydroxyprostaglandin dehydrogenase [15-PGDH] enzyme). In the present study, the associations of genotypic polymorphisms in COX-2 and 15-PGDH with SLE were investigated. Methods: One hundred and sixty SLE patients and 160 healthy controls participated in the study. The polymerase chain reaction -restriction fragments length polymorphism method was used for genotyping. The COX-2 rs2745557 G/A and 15-PGDH rs8752 G/A polymorphisms were investigated. Results:Regarding the COX-2 rs2745557 single nucleotide polymorphism, there was no significant association between COX-2 rs2745557 polymorphism and SLE.However, the dominant models showed a marginally significant relation (P = .048, odds ratio = 0.63, 95% CI = 0.4-1.0). Regarding GA genotype of 15-PGDH rd8752 polymorphism, there was a significant difference between two groups with a 4.5-fold increase in SLE development (P = .0001). The frequency of the A allele was higher in SLE patients than that in controls, showing a 1.4-fold increase in SLE development (P = .018). Conclusion:All results showed the protective effects of the dominant model of COX-2 rs2745557 polymorphism and risk factor of 15-PGDH rs8752 polymorphism on SLE development. K E Y W O R D S15-PGDH, COX-2, polymorphism, systemic lupus erythematosus Photosensitivity, n (%) 79 (49.4) Discoid rash, n (%) 6 (3.8) Mouth ulcers, n (%) 38 (23.8) Hair loss, n (%) 42 (26.3) Arthritis, n (%) 116 (72.5) Leukopenia, n (%) 30 (18.8) Thrombocytopenia, n (%) 35 (21.9) Renal disease, n (%) 21 (13.1) Antiphospholipid syndrome, n (%) 7 (4.4) Anti-double-stranded DNA, n (%) 108 (67.5) Antinuclear antibodies, n (%) 111 (69.4) Abbreviation: SLE, systemic lupus erythematosus. How to cite this article: Sandoughi M, Saravani M, Rokni M, Nora M, Mehrabani M, Dehghan A. Association between COX-2 and 15-PGDH polymorphisms and SLE susceptibility. Int J Rheum Dis. 2020;23:627-632. https ://doi.