Skip to main content

Advertisement

SpringerLink
Log in

HIPK3 Mediates Inflammatory Cytokines and Oxidative Stress Markers in Monocytes in a Rat Model of Sepsis Through the JNK/c-Jun Signaling Pathway

  • Original Article
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Sepsis is a fetal immunological disorder and its complication worsens in the patients with hemodialysis which may increase the risk of death. In the present study, we aimed to investigate the effect of homeodomain-interacting protein kinase 3 (HIPK3) on inflammatory factors and oxidative stress markers in monocytes of rats with sepsis by regulating the c-Jun amino-terminal kinase (JNK)/c-Jun signaling pathway. A rat model of sepsis was initially established using cecal ligation and puncture (CLP) and was further identified by enlarged spleen tissues, inflammation, and oxidative stress. Monocytes were isolated from rats with CLP-induced sepsis. HIPK3 was observed to be downregulated while JUN was upregulated in monocytes from rats with CLP-induced sepsis. Furthermore, isolated monocytes were transduced with lentiviral vectors expressing HIPK3 or shRNA against HIPK3 to explore the effect of HIPK3 on viability and apoptosis of monocytes as well as inflammatory factors and oxidative stress markers. The obtained data exhibited that overexpression of HIPK3 or inhibition of the JNK signaling pathway enhanced proliferation, reduced apoptosis of monocytes, alleviated inflammation, and oxidative stress injury. Consistently, our results may provide evidence that HIPK3 could inhibit the JNK/c-Jun signaling pathway, thereby potentially retarding the progression of sepsis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Data Availability

The datasets generated/analyzed during the current study are available.

References

  1. Winters, B.D., M. Eberlein, J. Leung, D.M. Needham, P.J. Pronovost, and J.E. Sevransky. 2010. Long-term mortality and quality of life in sepsis: a systematic review. Critical Care Medicine 38 (5): 1276–1283.

    Article  Google Scholar 

  2. Hotchkiss, R.S., G. Monneret, and D. Payen. 2013. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nature Reviews Immunology 13 (12): 862–874.

    Article  CAS  Google Scholar 

  3. Galley, H.F. 2011. Oxidative stress and mitochondrial dysfunction in sepsis. British Journal of Anaesthesia 107 (1): 57–64.

    Article  CAS  Google Scholar 

  4. Rhodes, A., L.E. Evans, W. Alhazzani, M.M. Levy, M. Antonelli, R. Ferrer, A. Kumar, J.E. Sevransky, C.L. Sprung, M.E. Nunnally, B. Rochwerg, G.D. Rubenfeld, D.C. Angus, D. Annane, R.J. Beale, G.J. Bellinghan, G.R. Bernard, J.D. Chiche, C. Coopersmith, D.P. De Backer, C.J. French, S. Fujishima, H. Gerlach, J.L. Hidalgo, S.M. Hollenberg, A.E. Jones, D.R. Karnad, R.M. Kleinpell, Y. Koh, T.C. Lisboa, F.R. Machado, J.J. Marini, J.C. Marshall, J.E. Mazuski, L.A. McIntyre, A.S. McLean, S. Mehta, R.P. Moreno, J. Myburgh, P. Navalesi, O. Nishida, T.M. Osborn, A. Perner, C.M. Plunkett, M. Ranieri, C.A. Schorr, M.A. Seckel, C.W. Seymour, L. Shieh, K.A. Shukri, S.Q. Simpson, M. Singer, B.T. Thompson, S.R. Townsend, T. Van der Poll, J.L. Vincent, W.J. Wiersinga, J.L. Zimmerman, and R.P. Dellinger. 2017. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. Intensive Care Medicine 43 (3): 304–377.

    Article  Google Scholar 

  5. Cecconi, M., L. Evans, M. Levy, and A. Rhodes. 2018. Sepsis and septic shock. Lancet 392 (10141): 75–87.

    Article  Google Scholar 

  6. Shalova, I.N., J.Y. Lim, M. Chittezhath, A.S. Zinkernagel, F. Beasley, E. Hernandez-Jimenez, V. Toledano, C. Cubillos-Zapata, A. Rapisarda, J. Chen, K. Duan, H. Yang, M. Poidinger, G. Melillo, V. Nizet, F. Arnalich, E. Lopez-Collazo, and S.K. Biswas. 2015. Human monocytes undergo functional re-programming during sepsis mediated by hypoxia-inducible factor-1alpha. Immunity 42 (3): 484–498.

    Article  CAS  Google Scholar 

  7. Mukherjee, R., P. Kanti Barman, P. Kumar Thatoi, R. Tripathy, B. Kumar Das, and B. Ravindran. 2015. Non-Classical monocytes display inflammatory features: Validation in Sepsis and Systemic Lupus Erythematous. Scientific Reports 5: 13886.

    Article  Google Scholar 

  8. Chen, J., and E.M. Verheyen. 2012. Homeodomain-interacting protein kinase regulates Yorkie activity to promote tissue growth. Current Biology 22 (17): 1582–1586.

    Article  CAS  Google Scholar 

  9. Blaquiere, J.A., and E.M. Verheyen. 2017. Homeodomain-Interacting Protein Kinases: Diverse and Complex Roles in Development and Disease. Current Topics in Developmental Biology 123: 73–103.

    Article  CAS  Google Scholar 

  10. Jiang, Z., L. Bo, Y. Meng, C. Wang, T. Chen, C. Wang, X. Yu, and X. Deng. 2018. Overexpression of homeodomain-interacting protein kinase 2 (HIPK2) attenuates sepsis-mediated liver injury by restoring autophagy. Cell Death & Disease 9 (9): 847.

    Article  Google Scholar 

  11. He, Q., J. Shi, H. Sun, J. An, Y. Huang, and M.S. Sheikh. 2010. Characterization of Human Homeodomain-interacting Protein Kinase 4 (HIPK4) as a Unique Member of the HIPK Family. Molecular and Cellular Pharmacology 2 (2): 61–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Arai, S., A. Matsushita, K. Du, K. Yagi, Y. Okazaki, and R. Kurokawa. 2007. Novel homeodomain-interacting protein kinase family member, HIPK4, phosphorylates human p53 at serine 9. FEBS Letters 581 (29): 5649–5657.

    Article  CAS  Google Scholar 

  13. Blaquiere, J.A., K.K.L. Wong, S.D. Kinsey, J. Wu, and E.M. Verheyen. 2018. Homeodomain-interacting protein kinase promotes tumorigenesis and metastatic cell behavior. Disease Models & Mechanisms 11 (1).

  14. Chen, C.L., C.F. Lin, W.T. Chang, W.C. Huang, C.F. Teng, and Y.S. Lin. 2008. Ceramide induces p38 MAPK and JNK activation through a mechanism involving a thioredoxin-interacting protein-mediated pathway. Blood 111 (8): 4365–4374.

    Article  CAS  Google Scholar 

  15. Sawai, M., Y. Ishikawa, A. Ota, and H. Sakurai. 2013. The proto-oncogene JUN is a target of the heat shock transcription factor HSF1. The FEBS Journal 280 (24): 6672–6680.

    Article  CAS  Google Scholar 

  16. Brandt, B., E.F. Abou-Eladab, M. Tiedge, and H. Walzel. 2010. Role of the JNK/c-Jun/AP-1 signaling pathway in galectin-1-induced T-cell death. Cell Death & Disease 1: e23.

    Article  CAS  Google Scholar 

  17. Nemeth, K., A. Leelahavanichkul, P.S. Yuen, B. Mayer, A. Parmelee, K. Doi, P.G. Robey, K. Leelahavanichkul, B.H. Koller, J.M. Brown, X. Hu, I. Jelinek, R.A. Star, and E. Mezey. 2009. Bone marrow stromal cells attenuate sepsis via prostaglandin E(2)-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nature Medicine 15 (1): 42–49.

    Article  CAS  Google Scholar 

  18. Kezic, J.M., and P.G. McMenamin. 2013. The effects of CX3CR1 deficiency and irradiation on the homing of monocyte-derived cell populations in the mouse eye. PLoS One 8 (7): e68570.

    Article  CAS  Google Scholar 

  19. Kim, D., and J.Y. Kim. 2014. Anti-CD14 antibody reduces LPS responsiveness via TLR4 internalization in human monocytes. Molecular Immunology 57 (2): 210–215.

    Article  CAS  Google Scholar 

  20. Pierrakos, C., and J.L. Vincent. 2010. Sepsis biomarkers: a review. Critical Care 14 (1): R15.

    Article  Google Scholar 

  21. Guerra, F.M., J.L. Gommerman, S.A. Corfe, C.J. Paige, and R. Rottapel. 2012. Homeodomain-interacting protein kinase (HIPK)-1 is required for splenic B cell homeostasis and optimal T-independent type 2 humoral response. PLoS One 7 (4): e35533.

    Article  CAS  Google Scholar 

  22. Lan, H.C., H.J. Li, G. Lin, P.Y. Lai, and B.C. Chung. 2007. Cyclic AMP stimulates SF-1-dependent CYP11A1 expression through homeodomain-interacting protein kinase 3-mediated Jun N-terminal kinase and c-Jun phosphorylation. Molecular and Cellular Biology 27 (6): 2027–2036.

    Article  CAS  Google Scholar 

  23. Lan, H.C., C.F. Wu, H.M. Shih, and B.C. Chung. 2012. Death-associated protein 6 (Daxx) mediates cAMP-dependent stimulation of Cyp11a1 (P450scc) transcription. The Journal of Biological Chemistry 287 (8): 5910–5916.

    Article  CAS  Google Scholar 

  24. Pizzino, G., A. Bitto, G. Pallio, N. Irrera, F. Galfo, M. Interdonato, A. Mecchio, F. De Luca, L. Minutoli, F. Squadrito, and D. Altavilla. 2015. Blockade of the JNK signalling as a rational therapeutic approach to modulate the early and late steps of the inflammatory cascade in polymicrobial sepsis. Mediators of Inflammation 2015: 591572.

    Article  Google Scholar 

  25. Venet, F., and G. Monneret. 2018. Advances in the understanding and treatment of sepsis-induced immunosuppression. Nature Reviews. Nephrology 14 (2): 121–137.

    Article  CAS  Google Scholar 

  26. Pelekanou, A., I. Tsangaris, A. Kotsaki, V. Karagianni, H. Giamarellou, A. Armaganidis, and E.J. Giamarellos-Bourboulis. 2009. Decrease of CD4-lymphocytes and apoptosis of CD14-monocytes are characteristic alterations in sepsis caused by ventilator-associated pneumonia: results from an observational study. Critical Care 13 (6): R172.

    Article  Google Scholar 

  27. Hotchkiss, R.S., and S. Opal. 2010. Immunotherapy for sepsis--a new approach against an ancient foe. The New England Journal of Medicine 363 (1): 87–89.

    Article  CAS  Google Scholar 

  28. Zhang, Y., Y. Zhou, J. Lou, J. Li, L. Bo, K. Zhu, X. Wan, X. Deng, and Z. Cai. 2010. PD-L1 blockade improves survival in experimental sepsis by inhibiting lymphocyte apoptosis and reversing monocyte dysfunction. Critical Care 14 (6): R220.

    Article  Google Scholar 

  29. Shan, K., C. Liu, B.H. Liu, X. Chen, R. Dong, X. Liu, Y.Y. Zhang, B. Liu, S.J. Zhang, J.J. Wang, S.H. Zhang, J.H. Wu, C. Zhao, and B. Yan. 2017. Circular Noncoding RNA HIPK3 Mediates Retinal Vascular Dysfunction in Diabetes Mellitus. Circulation 136 (17): 1629–1642.

    Article  CAS  Google Scholar 

  30. Lee, S.H., S.W. Park, C.W. Pyo, N.K. Yoo, J. Kim, and S.Y. Choi. 2009. Requirement of the JNK-associated Bcl-2 pathway for human lactoferrin-induced apoptosis in the Jurkat leukemia T cell line. Biochimie 91 (1): 102–108.

    Article  CAS  Google Scholar 

  31. Neisch, A.L., O. Speck, B. Stronach, and R.G. Fehon. 2010. Rho1 regulates apoptosis via activation of the JNK signaling pathway at the plasma membrane. The Journal of Cell Biology 189 (2): 311–323.

    Article  CAS  Google Scholar 

  32. Wang, H.Q., B.Q. Liu, Y.Y. Gao, X. Meng, Y. Guan, H.Y. Zhang, and Z.X. Du. 2009. Inhibition of the JNK signalling pathway enhances proteasome inhibitor-induced apoptosis of kidney cancer cells by suppression of BAG3 expression. British Journal of Pharmacology 158 (5): 1405–1412.

    Article  CAS  Google Scholar 

  33. Said, E.A., F.P. Dupuy, L. Trautmann, Y. Zhang, Y. Shi, M. El-Far, B.J. Hill, A. Noto, P. Ancuta, Y. Peretz, S.G. Fonseca, J. Van Grevenynghe, M.R. Boulassel, J. Bruneau, N.H. Shoukry, J.P. Routy, D.C. Douek, E.K. Haddad, and R.P. Sekaly. 2010. Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection. Nature Medicine 16 (4): 452–459.

    Article  CAS  Google Scholar 

  34. Urbahn, M.A., S.C. Kaup, F. Reusswig, I. Kruger, M. Spelleken, K. Jurk, M. Klier, P.A. Lang, and M. Elvers. 2018. Phospholipase D1 regulation of TNF-alpha protects against responses to LPS. Scientific Reports 8 (1): 10006.

    Article  Google Scholar 

  35. Li, R., J. Shang, W. Zhou, L. Jiang, D. Xie, and G. Tu. 2018. Overexpression of HIPK2 attenuates spinal cord injury in rats by modulating apoptosis, oxidative stress, and inflammation. Biomedicine & Pharmacotherapy 103: 127–134.

    Article  CAS  Google Scholar 

  36. Shen, J., T. Yang, Y. Xu, Y. Luo, X. Zhong, L. Shi, T. Hu, T. Guo, Y. Nie, F. Luo, and Q. Lin. 2018. delta-Tocotrienol, Isolated from Rice Bran, Exerts an Anti-Inflammatory Effect via MAPKs and PPARs Signaling Pathways in Lipopolysaccharide-Stimulated Macrophages. International Journal of Molecular Sciences 19 (10).

  37. Tao, J., Y. Wei, and T. Hu. 2016. Flavonoids of Polygonum hydropiper L. attenuates lipopolysaccharide-induced inflammatory injury via suppressing phosphorylation in MAPKs pathways. BMC Complementary and Alternative Medicine 16: 25.

    Article  Google Scholar 

  38. Kenzel, S., G. Mancuso, R. Malley, G. Teti, D.T. Golenbock, and P. Henneke. 2006. c-Jun kinase is a critical signaling molecule in a neonatal model of group B streptococcal sepsis. Journal of Immunology 176 (5): 3181–3188.

    Article  CAS  Google Scholar 

  39. Miksa, M., D. Amin, R. Wu, A. Jacob, M. Zhou, W. Dong, W.L. Yang, T.S. Ravikumar, and P. Wang. 2008. Maturation-induced down-regulation of MFG-E8 impairs apoptotic cell clearance and enhances endotoxin response. International Journal of Molecular Medicine 22 (6): 743–748.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Saito, C., J.J. Lemasters, and H. Jaeschke. 2010. c-Jun N-terminal kinase modulates oxidant stress and peroxynitrite formation independent of inducible nitric oxide synthase in acetaminophen hepatotoxicity. Toxicology and Applied Pharmacology 246 (1–2): 8–17.

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Ben Liu, Qiuyue Hou and Yuhong Ma contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Laboratory, The Affiliated Huai’an No. 1 People’s Hospital of Nanjing Medical University, No. 1 West Yellow River Road, Huai’an, 223300, Jiangsu, People’s Republic of China

    Ben Liu

  2. Department of Clinical Laboratory, Huaiyin Hospital of Huai’an City, 38 Beijing West Road, Huai’an, 223300, Jiangsu, People’s Republic of China

    Qiuyue Hou

  3. Department of Psychiatry, Huaian No. 3 People’s Hospital, 272 Huaihai West Road, Huai’an, 223300, Jiangsu, People’s Republic of China

    Yuhong Ma

  4. Department of Clinical Laboratory, Huai’an Hospital Affiliated of Xuzhou Medical University, No. 62, Huaihai South Road, Huai’an, 223002, Jiangsu Province, People’s Republic of China

    Xuehua Han

Authors
  1. Ben Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qiuyue Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuhong Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xuehua Han
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Ben Liu, QiuyueHou, Yuhong Ma, and Xuehua Han wrote the paper and conceived and designed the experiments; Ben Liu, Xuehua Han, and QiuyueHou analyzed the data; Ben Liu and Yuhong Ma collected the data for this study. All the authors have read and approved the final submitted manuscript.

Corresponding author

Correspondence to Xuehua Han.

Ethics declarations

All animal experiments were conducted under the approval of the Animal Ethics Committee of Huai’an Hospital Affiliated of Xuzhou Medical University. The experimental procedures were performed in compliance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health.

Competing Interests

The authors declare that there are no conflicts of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, B., Hou, Q., Ma, Y. et al. HIPK3 Mediates Inflammatory Cytokines and Oxidative Stress Markers in Monocytes in a Rat Model of Sepsis Through the JNK/c-Jun Signaling Pathway. Inflammation 43, 1127–1142 (2020). https://doi.org/10.1007/s10753-020-01200-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-020-01200-5

KEY WORDS

Search

Navigation