Chloroquine and Rapamycin Augment Interleukin-37 Expression via the LC3, ERK, and AP-1 Axis in the Presence of Lipopolysaccharides
IL-37 is a cytokine that plays critical protective roles in many metabolic inflammatory diseases, and its therapeutic potential has been confirmed by exogenous IL-37 administration. However, its regulatory mechanisms remain unclear. U937 cells were treated with autophagy-modifying reagents (3-MA, ch...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-01-01
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| Series: | Journal of Immunology Research |
| Online Access: | http://dx.doi.org/10.1155/2020/6457879 |
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| author | Xiaoyi Shi Chunhui Lai Lianyu Zhao Mingying Zhang Xi Liu Shanqin Peng Weizhong Guo Qiuying Xu Song Chen Guang-xing Chen |
| author_facet | Xiaoyi Shi Chunhui Lai Lianyu Zhao Mingying Zhang Xi Liu Shanqin Peng Weizhong Guo Qiuying Xu Song Chen Guang-xing Chen |
| author_sort | Xiaoyi Shi |
| collection | DOAJ |
| description | IL-37 is a cytokine that plays critical protective roles in many metabolic inflammatory diseases, and its therapeutic potential has been confirmed by exogenous IL-37 administration. However, its regulatory mechanisms remain unclear. U937 cells were treated with autophagy-modifying reagents (3-MA, chloroquine, and rapamycin) with or without LPS stimulation. Thereafter, IL-37 expression and autophagic markers (Beclin1, P62/SQSTM1, and LC3) were determined. For regulatory signal pathways, phosphorylated proteins of NF-κB (p65 and IκBα), AP-1 (c-Fos/c-Jun), and MAPK signal pathways (Erk1/2 and p38 MAPK) were quantified, and the agonists and antagonists of MAPK and NF-κB pathways were also used. Healthy human peripheral blood mononuclear cells were treated similarly to confirm our results. Four rhesus monkeys were also administered chloroquine to evaluate IL-37 induction in vivo and its bioactivity on CD4 proliferation and activation. IL-37 was upregulated by rapamycin and chloroquine in both U937 cells and human PBMCs in the presence of LPS. IL-37 was preferentially induced in autophagic cells associated with LC3 conversion. AP-1 and p65 binding motifs could be deduced in the sequence of the IL-37 promoter. Inductive IL-37 expression was accompanied with increased phosphorylated Erk1/2 and AP-1 and could be completely abolished by an Erk1/2 inhibitor or augmented by Erk1/2 agonists. In monkeys, chloroquine increased IL-37 expression, which was inversely correlated with CD4 proliferation and phosphorylated STAT3. IL-37 levels were induced by rapamycin and chloroquine through the LC3, Erk1/2, and NF-κB/AP-1 pathways. Functional IL-37 could also be induced in vivo. |
| format | Article |
| id | doaj-art-207fd47792584a7cb40ef31cbbe1d32c |
| institution | Kabale University |
| issn | 2314-8861 2314-7156 |
| language | English |
| publishDate | 2020-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Immunology Research |
| spelling | doaj-art-207fd47792584a7cb40ef31cbbe1d32c2025-02-03T05:49:31ZengWileyJournal of Immunology Research2314-88612314-71562020-01-01202010.1155/2020/64578796457879Chloroquine and Rapamycin Augment Interleukin-37 Expression via the LC3, ERK, and AP-1 Axis in the Presence of LipopolysaccharidesXiaoyi Shi0Chunhui Lai1Lianyu Zhao2Mingying Zhang3Xi Liu4Shanqin Peng5Weizhong Guo6Qiuying Xu7Song Chen8Guang-xing Chen9Guangzhou University of Chinese Medicine, Guangzhou 510405, ChinaScience and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou 510405, ChinaGuangzhou University of Chinese Medicine, Guangzhou 510405, ChinaDivision of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, ChinaGuangzhou University of Chinese Medicine, Guangzhou 510405, ChinaGuangzhou University of Chinese Medicine, Guangzhou 510405, ChinaGuangzhou University of Chinese Medicine, Guangzhou 510405, ChinaDivision of Rheumatology and Clinical Immunology, The First Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510405, ChinaGuangzhou University of Chinese Medicine, Guangzhou 510405, ChinaGuangzhou University of Chinese Medicine, Guangzhou 510405, ChinaIL-37 is a cytokine that plays critical protective roles in many metabolic inflammatory diseases, and its therapeutic potential has been confirmed by exogenous IL-37 administration. However, its regulatory mechanisms remain unclear. U937 cells were treated with autophagy-modifying reagents (3-MA, chloroquine, and rapamycin) with or without LPS stimulation. Thereafter, IL-37 expression and autophagic markers (Beclin1, P62/SQSTM1, and LC3) were determined. For regulatory signal pathways, phosphorylated proteins of NF-κB (p65 and IκBα), AP-1 (c-Fos/c-Jun), and MAPK signal pathways (Erk1/2 and p38 MAPK) were quantified, and the agonists and antagonists of MAPK and NF-κB pathways were also used. Healthy human peripheral blood mononuclear cells were treated similarly to confirm our results. Four rhesus monkeys were also administered chloroquine to evaluate IL-37 induction in vivo and its bioactivity on CD4 proliferation and activation. IL-37 was upregulated by rapamycin and chloroquine in both U937 cells and human PBMCs in the presence of LPS. IL-37 was preferentially induced in autophagic cells associated with LC3 conversion. AP-1 and p65 binding motifs could be deduced in the sequence of the IL-37 promoter. Inductive IL-37 expression was accompanied with increased phosphorylated Erk1/2 and AP-1 and could be completely abolished by an Erk1/2 inhibitor or augmented by Erk1/2 agonists. In monkeys, chloroquine increased IL-37 expression, which was inversely correlated with CD4 proliferation and phosphorylated STAT3. IL-37 levels were induced by rapamycin and chloroquine through the LC3, Erk1/2, and NF-κB/AP-1 pathways. Functional IL-37 could also be induced in vivo.http://dx.doi.org/10.1155/2020/6457879 |
| spellingShingle | Xiaoyi Shi Chunhui Lai Lianyu Zhao Mingying Zhang Xi Liu Shanqin Peng Weizhong Guo Qiuying Xu Song Chen Guang-xing Chen Chloroquine and Rapamycin Augment Interleukin-37 Expression via the LC3, ERK, and AP-1 Axis in the Presence of Lipopolysaccharides Journal of Immunology Research |
| title | Chloroquine and Rapamycin Augment Interleukin-37 Expression via the LC3, ERK, and AP-1 Axis in the Presence of Lipopolysaccharides |
| title_full | Chloroquine and Rapamycin Augment Interleukin-37 Expression via the LC3, ERK, and AP-1 Axis in the Presence of Lipopolysaccharides |
| title_fullStr | Chloroquine and Rapamycin Augment Interleukin-37 Expression via the LC3, ERK, and AP-1 Axis in the Presence of Lipopolysaccharides |
| title_full_unstemmed | Chloroquine and Rapamycin Augment Interleukin-37 Expression via the LC3, ERK, and AP-1 Axis in the Presence of Lipopolysaccharides |
| title_short | Chloroquine and Rapamycin Augment Interleukin-37 Expression via the LC3, ERK, and AP-1 Axis in the Presence of Lipopolysaccharides |
| title_sort | chloroquine and rapamycin augment interleukin 37 expression via the lc3 erk and ap 1 axis in the presence of lipopolysaccharides |
| url | http://dx.doi.org/10.1155/2020/6457879 |
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