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Cordycepin Attenuates IFN-γ-Induced Macrophage IP-10 and Mig Expressions by Inhibiting STAT1 Activity in CFA-Induced Inflammation Mice Model

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Abstract

Cordycepin, a natural derivative of adenosine, has been shown to exert pharmacological properties including anti-oxidation, antitumor, and immune regulation. It is reported that cordycepin is involved in the regulation of macrophage function. However, the effect of cordycepin on inflammatory cell infiltration in inflammation remains ambiguous. In this study, we investigated the potential role of cordycepin playing in macrophage function in CFA-induced inflammation mice model. In this model, we found that cordycepin prevented against macrophage infiltration in paw tissue and reduced interferon-γ (IFN-γ) production in both serum and paw tissue. Using luciferase reporter assay, we found that cordycepin suppressed IFN-γ-induced activators of transcription-1 (STAT1) transcriptional activity in a dose-dependent manner. Moreover, western blotting data demonstrated that cordycepin inhibited IFN-γ-induced STAT1 activation through attenuating STAT1 phosphorylation. Further investigations revealed that cordycepin inhibited the expressions of IFN-γ-inducible protein 10 (IP-10) and monokine induced by IFN-γ (Mig), which were the effector genes in IFN-γ-induced STAT1 signaling. Meanwhile, the excessive inflammatory cell infiltration in paw tissue was reduced by cordycepin. These findings demonstrate that cordycepin alleviates excessive inflammatory cell infiltration through down-regulation of macrophage IP-10 and Mig expressions via suppressing STAT1 phosphorylation. Thus, cordycepin may be a potential therapeutic approach to prevent and treat inflammation-associated diseases.

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References

  1. Gai, G.Z., S.J. Jin, B. Wang, Y.Q. Li, and C.X. Li. 2004. The efficacy of Cordyceps militaris capsules in treatment of chronic bronchitis in comparison with Jinshuibao capsules. Chinese New Drugs Journal 13: 169–171.

    Google Scholar 

  2. Mamta, S. Mehrotra, V. Amitabh, P. Kirar, S. Vats, P. Nandi, P.S. Negi, and K. Misra. 2015. Phytochemical and antimicrobial activities of Himalayan Cordyceps sinensis (Berk.) Sacc. Indian Journal of Experimental Biology 53 (1): 36–43.

    CAS  PubMed  Google Scholar 

  3. Ruma, I.M., E.W. Putranto, E. Kondo, R. Watanabe, K. Saito, Y. Inoue, K. Yamamoto, S. Nakata, M. Kaihata, H. Murata, and M. Sakaguchi. 2014. Extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells. International Journal of Oncology 45 (1): 209–218. https://doi.org/10.3892/ijo.2014.2397.

    Article  CAS  PubMed  Google Scholar 

  4. Choi, S.B., C.H. Park, M.K. Choi, D.W. Jun, and S. Park. 2004. Improvement of insulin resistance and insulin secretion by water extracts of Cordyceps militaris, Phellinus linteus, and Paecilomyces tenuipes in 90% pancreatectomized rats. Bioscience, Biotechnology, and Biochemistry 68 (11): 2257–2264. https://doi.org/10.1271/bbb.68.2257.

    Article  CAS  PubMed  Google Scholar 

  5. Cunningham, K.G., W. Manson, F.S. Spring, and S.A. Hutchinson. 1950. Cordycepin, a metabolic product isolated from cultures of Cordyceps militaris (Linn.) link. Nature 166 (4231): 949.

    Article  CAS  Google Scholar 

  6. Hsu, Peng Yang, Yueh Hsin Lin, Erh Ling Yeh, Hui Chen Lo, Tai Hao Hsu, and Su. Che Chun. 2017. Cordycepin and a preparation from Cordyceps militaris inhibit malignant transformation and proliferation by decreasing EGFR and IL-17RA signaling in a murine oral cancer model. Oncotarget 8 (55): 93712–93728.

    Article  Google Scholar 

  7. Sugar, A.M., and R.P. Mccaffrey. 1998. Antifungal activity of 3′-deoxyadenosine (cordycepin). Antimicrobial Agents and Chemotherapy 42 (6): 1424–1427.

    Article  CAS  Google Scholar 

  8. Mueller, Werner E.G., Barbara E. Weiler, Ramamurthy Charubala, Wolfgang Pfleiderer, Leserman Lee, Robert W. Sobol, Robert J. Suhadolnik, and Heinz C. Schroeder. 1991. Cordycepin analogs of 2′,5′-oligoadenylate inhibit human immunodeficiency virus infection via inhibition of reverse transcriptase. Biochemistry 30 (8): 2027–2033.

    Article  CAS  Google Scholar 

  9. Qing, R., Z. Huang, Y. Tang, Q. Xiang, and F. Yang. 2018. Cordycepin alleviates lipopolysaccharide-induced acute lung injury via Nrf2/HO-1 pathway. International Immunopharmacology 60: 18–25.

    Article  CAS  Google Scholar 

  10. Tianzhu, Z., Y. Shihai, and D. Juan. 2015. The effects of Cordycepin on ovalbumin-induced allergic inflammation by strengthening Treg response and suppressing Th17 responses in ovalbumin-sensitized mice. Inflammation 38 (3): 1036–1043.

    Article  Google Scholar 

  11. Choi, Y.H., G.Y. Kim, and H.H. Lee. 2014. Anti-inflammatory effects of cordycepin in lipopolysaccharide-stimulated RAW 264.7 macrophages through toll-like receptor 4-mediated suppression of mitogen-activated protein kinases and NF-kappaB signaling pathways. Drug Design, Development and Therapy 8: 1941–1953. https://doi.org/10.2147/DDDT.S71957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Li, Y., K. Li, L. Mao, X. Han, K. Zhang, C. Zhao, and J. Zhao. 2016. Cordycepin inhibits LPS-induced inflammatory and matrix degradation in the intervertebral disc. PeerJ 4: e1992. https://doi.org/10.7717/peerj.1992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ren, Z., J. Cui, Z. Huo, J. Xue, H. Cui, B. Luo, L. Jiang, and R. Yang. 2012. Cordycepin suppresses TNF-alpha-induced NF-kappaB activation by reducing p65 transcriptional activity, inhibiting IkappaBalpha phosphorylation, and blocking IKKgamma ubiquitination. International Immunopharmacology 14 (4): 698–703. https://doi.org/10.1016/j.intimp.2012.10.008.

    Article  CAS  PubMed  Google Scholar 

  14. Martinez-Martinez, L., M.T. Martinez-Saavedra, P. Fuentes-Prior, M. Barnadas, M.V. Rubiales, J. Noda, I. Badell, C. Rodriguez-Gallego, and O. de la Calle-Martin. 2015. A novel gain-of-function STAT1 mutation resulting in basal phosphorylation of STAT1 and increased distal IFN-gamma-mediated responses in chronic mucocutaneous candidiasis. Molecular Immunology 68 (2 Pt C): 597–605. https://doi.org/10.1016/j.molimm.2015.09.014.

    Article  CAS  PubMed  Google Scholar 

  15. Rawlings, J.S., K.M. Rosler, and D.A. Harrison. 2004. The JAK/STAT signaling pathway. Journal of Cell Science 117 (Pt 8): 1281–1283. https://doi.org/10.1242/jcs.00963.

    Article  CAS  PubMed  Google Scholar 

  16. Park, O.J., M.K. Cho, C.H. Yun, and S.H. Han. 2015. Lipopolysaccharide of Aggregatibacter actinomycetemcomitans induces the expression of chemokines MCP-1, MIP-1alpha, and IP-10 via similar but distinct signaling pathways in murine macrophages. Immunobiology 220 (9): 1067–1074. https://doi.org/10.1016/j.imbio.2015.05.008.

    Article  CAS  PubMed  Google Scholar 

  17. Xu, Q., Y. Zhou, R. Zhang, Z. Sun, and L.F. Cheng. 2017. Antiarthritic activity of Qi-Wu rheumatism granule (a Chinese herbal compound) on complete Freund's adjuvant-induced arthritis in rats. Evidence-based Complementary and Alternative Medicine 2017: 1960517. https://doi.org/10.1155/2017/1960517.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Dong, L., J. Zhu, H. Du, H. Nong, X. He, and X. Chen. 2017. Astilbin from Smilax glabra Roxb. Attenuates inflammatory responses in complete Freund's adjuvant-induced arthritis rats. Evidence-based Complementary and Alternative Medicine 2017: 8246420. https://doi.org/10.1155/2017/8246420.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Robledo-Gonzalez, L.E., A. Martinez-Martinez, V.M. Vargas-Munoz, R.I. Acosta-Gonzalez, R. Plancarte-Sanchez, M. Anaya-Reyes, C. Fernandez Del Valle-Laisequilla, J.G. Reyes-Garcia, and J.M. Jimenez-Andrade. 2017. Repeated administration of mazindol reduces spontaneous pain-related behaviors without modifying bone density and microarchitecture in a mouse model of complete Freund's adjuvant-induced knee arthritis. Journal of Pain Research 10: 1777–1786. https://doi.org/10.2147/JPR.S136581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Arango Duque, G., and A. Descoteaux. 2014. Macrophage cytokines: Involvement in immunity and infectious diseases. Frontiers in Immunology 5: 491. https://doi.org/10.3389/fimmu.2014.00491.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hristodorov, D., R. Mladenov, M. Huhn, S. Barth, and T. Thepen. 2012. Macrophage-targeted therapy: CD64-based immunotoxins for treatment of chronic inflammatory diseases. Toxins (Basel) 4 (9): 676–694. https://doi.org/10.3390/toxins4090676.

    Article  CAS  Google Scholar 

  22. Medzhitov, R. 2010. Inflammation 2010: New adventures of an old flame. Cell 140 (6): 771–776. https://doi.org/10.1016/j.cell.2010.03.006.

    Article  CAS  PubMed  Google Scholar 

  23. Malyshev, I.Y. 1900. Phenomena and signaling mechanisms of macrophage reprogramming. Patologicheskaia Fiziologiia i Eksperimentalnaia Terapiia 59 (2): 99–111.

    Google Scholar 

  24. Zhang, Da-wei, Zhen-lin Wang, Wei Qi, Wei Lei, and Guang-yue Zhao. 2014. Cordycepin (3′-deoxyadenosine) down-regulates the proinflammatory cytokines in inflammation-induced osteoporosis model. Inflammation 37 (4): 1044–1049.

    Article  CAS  Google Scholar 

  25. Yarilina, Anna, Kai Xu, Chunhin Chan, and Lionel B. Ivashkiv. 2012. Regulation of inflammatory responses in tumor necrosis factor-activated and rheumatoid arthritis synovial macrophages by JAK inhibitors. Arthritis & Rheumatology 64 (12): 3856–3866.

    Article  CAS  Google Scholar 

  26. Morrow, A.N., H. Schmeisser, T. Tsuno, and K.C. Zoon. 2011. A novel role for IFN-stimulated gene factor 3II in IFN-γ signaling and induction of antiviral activity in human cells. Journal of Immunology 186 (3): 1685–1693.

    Article  CAS  Google Scholar 

  27. Yuan, S., T. Zheng, P. Li, R. Yang, J. Ruan, S. Huang, Z. Wu, and A. Xu. 2015. Characterization of Amphioxus IFN regulatory factor family reveals an archaic signaling framework for innate immune response. Journal of Immunology 195 (12): 5657–5666. https://doi.org/10.4049/jimmunol.1501927.

    Article  CAS  Google Scholar 

  28. Huang, S.G., W.L. Guo, Z.C. Zhou, J.J. Li, F.B. Yang, and J. Wang. 2016. Altered expression levels of occludin, claudin-1 and myosin light chain kinase in the common bile duct of pediatric patients with pancreaticobiliary maljunction. BMC Gastroenterology 16: 7–7. https://doi.org/10.1186/s12876-016-0416-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mady, H.H., and M.F. Melhem. 2002. FHIT protein expression and its relation to apoptosis, tumor histologic grade and prognosis in colorectal adenocarcinoma: An immunohistochemical and image analysis study. Clinical & Experimental Metastasis 19 (4): 351–358.

    Article  CAS  Google Scholar 

  30. Munder, M., M. Mallo, K. Eichmann, and M. Modolell. 1998. Murine macrophages secrete interferon gamma upon combined stimulation with interleukin (IL)-12 and IL-18: A novel pathway of autocrine macrophage activation. The Journal of Experimental Medicine 187 (12): 2103–2108. https://doi.org/10.1084/jem.187.12.2103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Liu, Q., Y.L. Zhang, W. Hu, S.P. Hu, Z. Zhang, X.H. Cai, and X.J. He. 2018. Transcriptome of porcine alveolar macrophages activated by interferon-gamma and lipopolysaccharide. Biochemical and Biophysical Research Communications 503 (4): 2666–2672. https://doi.org/10.1016/j.bbrc.2018.08.021.

    Article  CAS  PubMed  Google Scholar 

  32. Jaruga, B., F. Hong, W.H. Kim, and B. Gao. 2003. IFN-gamma/STAT1 acts as a proinflammatory signal in T cell-mediated hepatitis via induction of multiple chemokines and adhesion molecules: A critical role of IRF-1. Hepatology 38 (5): G1044.

    Google Scholar 

  33. Weiss, Günter, and Ulrich E. Schaible. 2015. Macrophage defense mechanisms against intracellular bacteria. Immunological Reviews 264 (1): 182–203.

    Article  CAS  Google Scholar 

  34. Gregory, J.L., E.F. Morand, S.J. McKeown, J.A. Ralph, P. Hall, Y.H. Yang, S.R. McColl, and M.J. Hickey. 2006. Macrophage migration inhibitory factor induces macrophage recruitment via CC chemokine ligand 2. Journal of Immunology 177 (11): 8072–8079.

    Article  CAS  Google Scholar 

  35. Gordon, S. 1998. The role of the macrophage in immune regulation. Research in Immunology 149 (7–8): 685–688.

    Article  CAS  Google Scholar 

  36. Meda, L., M.A. Cassatella, G.I. Szendrei, L. Otvos Jr., P. Baron, M. Villalba, D. Ferrari, and F. Rossi. 1995. Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature 374 (6523): 647–650. https://doi.org/10.1038/374647a0.

    Article  CAS  PubMed  Google Scholar 

  37. Dandona, P., A. Chaudhuri, and S. Dhindsa. 2010. Proinflammatory and prothrombotic effects of hypoglycemia. Diabetes Care 33 (7): 1686–1687. https://doi.org/10.2337/dc10-0503.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Li, Jin, Liping Zhong, Haibo Zhu, and Fengzhong Wang. 2017. The Protective Effect of Cordycepin on D-Galactosamine/Lipopolysaccharide-Induced Acute Liver Injury. Mediators of Inflammation,2017,(2017-3-28) 2017 (1): 3946706.

    Google Scholar 

  39. Zhang, D.W., Z.L. Wang, W. Qi, W. Lei, and G.Y. Zhao. 2014. Cordycepin (3′-deoxyadenosine) down-regulates the proinflammatory cytokines in inflammation-induced osteoporosis model. Inflammation 37 (4): 1044–1049. https://doi.org/10.1007/s10753-014-9827-z.

    Article  CAS  PubMed  Google Scholar 

  40. Lei, J., Y. Wei, P. Song, Y. Li, T. Zhang, Q. Feng, and G. Xu. 2018. Cordycepin inhibits LPS-induced acute lung injury by inhibiting inflammation and oxidative stress. European Journal of Pharmacology 818: 110–114. https://doi.org/10.1016/j.ejphar.2017.10.029.

    Article  CAS  PubMed  Google Scholar 

  41. Shin, S., S. Moon, Y. Park, J. Kwon, S. Lee, C.K. Lee, K. Cho, N.J. Ha, and K. Kim. 2009. Role of Cordycepin and adenosine on the phenotypic switch of macrophages via induced anti-inflammatory cytokines. Immune Network 9 (6): 255–264. https://doi.org/10.4110/in.2009.9.6.255.

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by the Guangxi Natural Science Foundation Program (2018GXNSFAA281211), the National Natural Science Foundation of China (81360312 and 81402306), and the Science and Technology Research Project of the Guangxi Colleges and Universities (YB2014080).

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  1. Rirong Yang and Xiaoli Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Immunology, School of Preclinical Medicine, Center for Genomic and Personalized Medicine, Guangxi Medical University, 22 Shuangyong Road, Nanning, Guangxi, 530021, People’s Republic of China

    Rirong Yang, Xiaoli Wang, Deshuang Xi, Jian Mo & Shunrong Luo

  2. Department of Physiology, School of Preclinical Medicine, Guangxi Medical University, 22 Shuangyong Road, Nanning, Guangxi, 530021, People’s Republic of China

    Ke Wang, Jiao Wei & Hui Pang

  3. State Key Laboratory of Biocontrol, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, National Engineering Research Center of South China Sea Marine Biotechnology, Department of Biochemistry, College of Life Sciences, Sun Yat-sen University, Guangzhou, 510275, People’s Republic of China

    Zhenghua Ren

  4. Department of Clinical Laboratory, Peoples’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, 530021, People’s Republic of China

    Yu Luo

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  1. Rirong Yang
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Yang, R., Wang, X., Xi, D. et al. Cordycepin Attenuates IFN-γ-Induced Macrophage IP-10 and Mig Expressions by Inhibiting STAT1 Activity in CFA-Induced Inflammation Mice Model. Inflammation 43, 752–764 (2020). https://doi.org/10.1007/s10753-019-01162-3

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