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CIAP1/2 inhibition synergizes with TNF inhibition in autoimmunity by down-regulating IL-17A and inducing T_regs.

ABSTRACT: IL-17 and TNF-? are major effector cytokines in chronic inflammation. TNF-? inhibitors have revolutionized the treatment of rheumatoid arthritis (RA), although not all patients respond, and most relapse after treatment withdrawal. This may be due to a paradoxical exacerbation of T_H17 responses by TNF-? inhibition. We examined the therapeutic potential of targeting cellular inhibitors of apoptosis 1 and 2 (cIAP1/2) in inflammation by its influence on human T_H subsets and mice with collagen-induced arthritis. Inhibition of cIAP1/2 abrogated CD4⁺ IL-17A differentiation and IL-17 production. This was a direct effect on T cells, mediated by reducing NFATc1 expression. In mice, cIAP1/2 inhibition, when combined with etanercept, abrogated disease activity, which was associated with an increase in T_regs and was sustained after therapy retraction. We reveal an unexpected role for cIAP1/2 in regulating the balance between T_H17 and T_regs and suggest that combined therapeutic inhibition could induce long-term remission in inflammatory diseases.

SUBMITTER: Kawalkowska JZ

PROVIDER: S-EPMC6494502 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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cIAP1/2 inhibition synergizes with TNF inhibition in autoimmunity by down-regulating IL-17A and inducing Tregs.

Kawalkowska Joanna Z JZ Ogbechi Joy J Venables Patrick J PJ Williams Richard O RO

Science advances 20190501 5

IL-17 and TNF-α are major effector cytokines in chronic inflammation. TNF-α inhibitors have revolutionized the treatment of rheumatoid arthritis (RA), although not all patients respond, and most relapse after treatment withdrawal. This may be due to a paradoxical exacerbation of TH17 responses by TNF-α inhibition. We examined the therapeutic potential of targeting cellular inhibitors of apoptosis 1 and 2 (cIAP1/2) in inflammation by its influence on human TH subsets and mic ...[more]

PMID: 31049403

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Project description:BackgroundOxaliplatin is one of the most commonly used chemotherapeutic agent for the treatment of various cancers, including gastric cancer. It has, however, a narrow therapeutic index due to its toxicity and the occurrence of drug resistance. Hence, it is of great significance to develop novel therapies to potentiate the anti-tumor effect and reduce the toxicity of oxaliplatin. In our previous study, we demonstrated that ethaselen (BBSKE), an inhibitor of thioredoxin reductase, effectively inhibited the growth of gastric cancer cells and promoted apoptosis in vitro. In the present study, we investigated whether BBSKE can potentiate the anti-tumor effect of oxaliplatin in gastric cancer in vivo and vitro.MethodsCellular apoptosis and ROS levels were analyzed by flow cytometry. Thioredoxin reductase 1 (TrxR1) activity in gastric cancer cells, organoid and tumor tissues was determined by using the endpoint insulin reduction assay. Western blot was used to analyze the expressions of the indicated proteins. Nude mice xenograft models were used to test the effects of BBSKE and oxaliplatin combinations on gastric cancer cell growth in vivo. In addition, we also used the combined treatment of BBSKE and oxaliplatin in three cases of gastric cancer Patient-Derived organoid (GC-PDO) to detect the anti-tumor effect.ResultsWe found that BBSKE significantly enhanced oxaliplatin-induced growth inhibition in gastric cancer cells by inhibiting TrxR1 activity. Because of the inhibition of TrxR1 activity, BBSKE synergized with oxaliplatin to enhance the production of ROS and activate p38 and JNK signaling pathways which eventually induced apoptosis of gastric cancer cells. In vivo, we also found that BBSKE synergized with oxaliplatin to suppress the gastric cancer tumor growth in xenograft nude mice model, accompanied by the reduced TrxR1 activity. Remarkably, we found that BBSKE attenuated body weight loss evoked by oxaliplatin treatment. We also used three cases of GC-PDO and found that the combined treatment of BBSKE and oxaliplatin dramatically inhibited the growth and viability of GC-PDO with increased ROS level, decreased TrxR1 activity and enhanced apoptosis.ConclusionsThis study elucidates the underlying mechanisms of synergistic effect of BBSKE and oxaliplatin, and suggests that the combined treatment has potential value in gastric cancer therapy.

Project description:Background and Purpose: Although trastuzumab has shown considerable activity in the treatment of HER2-positive breast and gastric cancers, a significant proportion of patients do not respond to trastuzumab. Recent studies revealed that osthole, an active coumarin isolated from Cnidium monnieri (L.) Cusson possesses potent anti-tumor activity. Here, we for the first time investigated the anti-tumor activity of trastuzumab in combination with osthole in HER2-overexpressing cancers. Materials and Methods: N87 and SK-BR-3 cell lines, which were HER2-overexpressing cancer cells were used in our study. Cell Counting Kit-8 (CCK-8) assay was utilized to test the inhibitory effects of trastuzumab plus osthole. Combination index (CI) values were calculated using the Chou-Talalay method. Fluorescence-Activated Cell Sorter (FACS) assay was used to examine the cell cycle change and apoptosis upon combinatorial treatment. N87 tumor xenografts were established to evaluate in vivo effects of trastuzumab plus osthole. In addition, molecular mechanisms were analyzed by Western blot in vitro and in vivo. Results: As shown in our study, osthole alone exhibited effective anti-tumor activity against HER2-overexpressed N87 gastric cancer cells and SK-BR-3 breast cancer cells, which may be attributed to cell cycle arrest on G2/M phase and apoptosis. More importantly, our data demonstrated that trastuzumab plus osthole was much more potent than either agent alone in inhibiting the growth of N87 cancer cells in vitro and in vivo, which may be partly explained by the enhanced apoptosis upon the combinatorial treatment. Besides these, we also observed a significant decrease on the phosphorylation of AKT and MAPK in N87 cells when treated with trastuzumab plus osthole compared to either agent alone. Further data from N87 tumor xenografts revealed that trastuzumab plus osthole exerted their synergistic effects mainly on AKT signaling pathway. Conclusion: Collectively, these results support the clinical development of combination osthole with trastuzumab for the treatment of HER2-overexpressed gastric cancer.

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CIAP1/2 inhibition synergizes with TNF inhibition in autoimmunity by down-regulating IL-17A and inducing T_regs.

Publications

cIAP1/2 inhibition synergizes with TNF inhibition in autoimmunity by down-regulating IL-17A and inducing T<sub>regs</sub>.

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Dataset Information

CIAP1/2 inhibition synergizes with TNF inhibition in autoimmunity by down-regulating IL-17A and inducing Tregs.

Publications

cIAP1/2 inhibition synergizes with TNF inhibition in autoimmunity by down-regulating IL-17A and inducing T<sub>regs</sub>.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

CIAP1/2 inhibition synergizes with TNF inhibition in autoimmunity by down-regulating IL-17A and inducing T_regs.