Molecular and Cellular Biochemistry

, Volume 380, Issue 1–2, pp 249–257 | Cite as

The activation of HMGB1 as a progression factor on inflammation response in normal human bronchial epithelial cells through RAGE/JNK/NF-κB pathway

  • Xiaojin Wu
  • Yanyan Mi
  • Hui Yang
  • Ankang Hu
  • Qingguo Zhang
  • Chunli Shang


Extracellular high-mobility group box-1 (HMGB-1) has been implicated in the inflammation response leading to the precancerous lesions of non-small cell lung cancer (NSCLC). However, the role of HMGB-1 in the inflammation response in normal human bronchial epithelial (NHBE) cells and its underlying mechanisms were still not fully understood. In this study, the inflammation response in NHBE cells was stimulated by 2.5, 5, and 10 μg/ml HMGB-1. However, the receptor for advanced glycation end products (RAGE) blocker RAGE-Ab (5 μg/ml) or 10 μM c-Jun N-terminal kinases (JNK) inhibitor SP600125 could inhibit HMGB1-induced the release of inflammation cytokines including TNF-α, IL-8, IL-10, and MCP-1 in a dose-dependent manner. Furthermore, HMGB1-induced RAGE protein expression, JNK and NF-κB activation were attenuated by the pretreatment with RAGE-Ab or JNK inhibitor SP600125 in Western blot analysis. Our data indicated that HMGB-1 induced inflammation response in NHBE cells through activating RAGE/JNK/NF-κB pathway. HMGB-1 could act as a therapeutic target for inflammation leading NHBE cells to the precancerous lesions of NSCLC.


HMGB-1 Inflammation Normal human bronchial epithelial cells NSCLC RAGE JNK 



This study was supported by grants from the National Natural Science Foundation of China (No. 81172503).

Conflict of interest

We declare that there is no conflict of interest. No author has any financial interest or conflict of interest involved with this study.


  1. 1.
    Chunhacha P, Chanvorachote P (2012) Roles of caveolin-1 on anoikis resistance in non small cell lung cancer. Int J Physiol Pathophysiol Pharmacol 4:149–155PubMedCentralPubMedGoogle Scholar
  2. 2.
    Emmendoerffer A, Hecht M, Boeker T, Mueller M, Heinrich U (2000) Role of inflammation in chemical-induced lung cancer. Toxicol Lett 112–113:185–191PubMedCrossRefGoogle Scholar
  3. 3.
    Corrales L, Ajona D, Rafail S, Lasarte JJ, Riezu-Boj JI, Lambris JD, Rouzaut A, Pajares MJ, Montuenga LM, Pio R (2012) Anaphylatoxin c5a creates a favorable microenvironment for lung cancer progression. J Immuno 189:4674–4683CrossRefGoogle Scholar
  4. 4.
    Tao Y, Gu YJ, Cao ZH, Bian XJ, Lan T, Sang JR, Jiang L, Wang Y, Qian H, Chen YC (2012) Endogenous cGMP-dependent protein kinase reverses EGF-induced MAPK/ERK signal transduction through phosphorylation of VASP at Ser239. Oncol Lett 4:1104–1108PubMedCentralPubMedGoogle Scholar
  5. 5.
    Houghton AM (2012) Endogenous modifiers of cigarette smoke exposure within the lung. Proc Am Thorac Soc 9:66–68PubMedCrossRefGoogle Scholar
  6. 6.
    Smolarczyk R, Cichoń T, Jarosz M, Szala S (2012) HMGB1-its role in tumor progression and anticancer therapy. Postepy Hig Med Dosw (Online) 66:913–920CrossRefGoogle Scholar
  7. 7.
    Luo Y, Chihara Y, Fujimoto K, Sasahira T, Kuwada M, Fujiwara R, Fujii K, Ohmori H, Kuniyasu H (2012) High mobility group box 1 released from necrotic cells enhances regrowth and metastasis of cancer cells that have survived chemotherapy. Eur J Cancer. doi:10.1016/j.ejca.2012.09.016 Google Scholar
  8. 8.
    Naglova H, Bucova M (2012) HMGB1 and its physiological and pathological roles. Bratisl Lek Listy 113:163–171PubMedGoogle Scholar
  9. 9.
    Nogueira-Machado JA, de Oliveira Volpe CM (2012) HMGB-1 as a target for inflammation controlling. Recent Pat Endocr Metab Immune Drug Discov 6:201–209PubMedCrossRefGoogle Scholar
  10. 10.
    Logsdon CD, Fuentes MK, Huang EH, Arumugam T (2007) RAGE and RAGE ligands in cancer. Curr Mol Med 7:777–789PubMedCrossRefGoogle Scholar
  11. 11.
    Khan A, Vaibhav K, Javed H, Khan MM, Tabassum R, Ahmed ME, Srivastava P, Khuwaja G, Islam F, Siddiqui MS, Shafi MM, Islam F (2012) Attenuation of Aβ-induced neurotoxicity by thymoquinone via inhibition of mitochondrial dysfunction and oxidative stress. Mol Cell Biochem 369:55–65PubMedCrossRefGoogle Scholar
  12. 12.
    Xu Y, Feng L, Wang S, Zhu Q, Lin J, Lou C, Xiang P, He B, Zheng Z, Tang D, Zuo G (2011) Phytoestrogen calycosin-7-O-β-D-glucopyranoside ameliorates advanced glycation end products-induced HUVEC damage. J Cell Biochem 112:2953–2965PubMedCrossRefGoogle Scholar
  13. 13.
    Zhang Y, Dong J, He P, Li W, Zhang Q, Li N, Sun T (2012) Genistein inhibit cytokines or growth factor-induced proliferation and transformation phenotype in fibroblast-like synoviocytes of rheumatoid arthritis. Inflammation 35:377–387PubMedCrossRefGoogle Scholar
  14. 14.
    Mantell LL, Parrish WR, Ulloa L (2006) Hmgb-1 as a therapeutic target for infectious and inflammatory disorders. Shock 25:4–11PubMedCrossRefGoogle Scholar
  15. 15.
    Ohmori H, Luo Y, Kuniyasu H (2011) Non-histone nuclear factor HMGB1 as a therapeutic target in colorectal cancer. Expert Opin Ther Targets 15:183–193PubMedCrossRefGoogle Scholar
  16. 16.
    Nogueira-Machado JA, de Oliveira Volpe CM (2012) HMGB-1 as a target for inflammation controlling. Recent Pat Endocr Metab Immune Drug Discov 6:201–209PubMedCrossRefGoogle Scholar
  17. 17.
    Bezerra FS, Valença SS, Pires KM, Lanzetti M, Pimenta WA, Schmidt AC, Porto LC, Zin WA (2011) Long-term exposure to cigarette smoke impairs lung function and increases HMGB-1 expression in mice. Respir Physiol Neurobiol 177:120–126PubMedCrossRefGoogle Scholar
  18. 18.
    Choi J, Lee MK, Oh KH, Kim YS, Choi HY, Baek SK, Jung KY, Woo JS, Lee SH, Kwon SY (2011) Interaction effect between the receptor for advanced glycation end products (RAGE) and high-mobility group box-1 (HMGB-1) for the migration of a squamous cell carcinoma cell line. Tumori 97:196–202PubMedGoogle Scholar
  19. 19.
    Feng L, Zhu M, Zhang M, Jia X, Cheng X, Ding S, Zhu Q (2012) Amelioration of compound 4, 4′-diphenylmethane-bis(methyl)carbamate on high mobility group box1-mediated inflammation and oxidant stress responses in human umbilical vein endothelial cells via RAGE/ERK1/2/NF-κB pathway. Int Immunopharmacol 15:206–216. doi:10.1016/j.intimp.2012.11.015 PubMedCrossRefGoogle Scholar
  20. 20.
    Gupta A, Srivastava S, Prasad R, Natu SM, Mittal B, Negi MP, Srivastava AN (2010) Oxidative stress in non-small cell lung cancer patients after chemotherapy: association with treatment response. Respirology 15:349–356PubMedCrossRefGoogle Scholar
  21. 21.
    Tertil M, Jozkowicz A, Dulak J (2010) Oxidative stress in tumor angiogenesis-therapeutic targets. Curr Pharm Des 16:3877–3894PubMedCrossRefGoogle Scholar
  22. 22.
    Lau ST, Lin ZX, Leung PS (2010) Role of reactive oxygen species in brucein D-mediated p38-mitogen-activated protein kinase and nuclear factor-kappaB signalling pathways in human pancreatic adenocarcinoma cells. Br J Cancer 102:583–593PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Dejean E, Foisseau M, Lagarrigue F, Lamant L, Prade N, Marfak A, Delsol G, Giuriato S, Gaits-Iacovoni F, Meggetto F (2012) ALK + ALCLs induce cutaneous, HMGB-1-dependent IL-8/CXCL8 production by keratinocytes through NF-κB activation. Blood 119:4698–4707PubMedCrossRefGoogle Scholar
  24. 24.
    Sabapathy K (2012) Role of the JNK pathway in human diseases. Prog Mol Biol Transl Sci 106:145–169PubMedCrossRefGoogle Scholar
  25. 25.
    Könczöl M, Ebeling S, Goldenberg E, Treude F, Gminski R, Gieré R, Grobéty B, Rothen-Rutishauser B, Merfort I, Mersch-Sundermann V (2011) Cytotoxicity and genotoxicity of size-fractionated iron oxide (magnetite) in A549 human lung epithelial cells: role of ROS, JNK, and NF-κB. Chem Res Toxicol 24:1460–1475PubMedCrossRefGoogle Scholar
  26. 26.
    Xu H, Yao Y, Su Z, Yang Y, Kao R, Martin CM, Rui T (2011) Endogenous HMGB1 contributes to ischemia-reperfusion-induced myocardial apoptosis by potentiating the effect of TNF-α/JNK. Am J Physiol Heart Circ Physiol 300:H913–H921PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Warmka JK, Solberg EL, Zeliadt NA, Srinivasan B, Charlson AT, Xing C, Wattenberg EV (2012) Inhibition of mitogen activated protein kinases increases the sensitivity of A549 lung cancer cells to the cytotoxicity induced by a kava chalcone analog. Biochem Biophys Res Commun 424:488–492PubMedCentralPubMedCrossRefGoogle Scholar
  28. 28.
    Wu N, Gu C, Gu H, Hu H, Han Y, Li Q (2011) Metformin induces apoptosis of lung cancer cells through activating JNK/p38 MAPK pathway and GADD153. Neoplasma 58:482–490PubMedCrossRefGoogle Scholar
  29. 29.
    Yang L, Shi GL, Song CX, Xu SF (2010) Relationship between genetic polymorphism of MCP-1 and non-small-cell lung cancer in the Han nationality of North China. Genet Mol Res 9:765–771PubMedCrossRefGoogle Scholar
  30. 30.
    Zhang XW, Qin X, Qin CY, Yin YL, Chen Y, Zhu HL (2013) Expression of monocyte chemoattractant protein-1 and CC chemokine receptor 2 in non-small cell lung cancer and its significance. Cancer Immunol Immunother 62:563–570 Google Scholar
  31. 31.
    Nakasone Y, Fujimoto M, Matsushita T, Hamaguchi Y, Huu DL, Yanaba M, Sato S, Takehara K, Hasegawa M (2012) Host-derived MCP-1 and MIP-1α regulate protective anti-tumor immunity to localized and metastatic B16 melanoma. Am J Pathol 180:365–374PubMedCrossRefGoogle Scholar
  32. 32.
    Zhou JG, Dong JY, Zhang LH, Wang J (2011) Expression of high mobility group box chromosomal protein 1 in mice with lupus nephritis. Zhejiang Da Xue Xue Bao Yi Xue Ban 40:200–206PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Xiaojin Wu
    • 1
  • Yanyan Mi
    • 2
  • Hui Yang
    • 3
  • Ankang Hu
    • 2
  • Qingguo Zhang
    • 3
  • Chunli Shang
    • 4
  1. 1.Department of Radiation OncologyThe First People’s Hospital of XuzhouXuzhouPeople’s Republic of China
  2. 2.Department of PharmacyXuzhou Medical CollegeXuzhouPeople’s Republic of China
  3. 3.Department of NeurosurgeryThe First People’s Hospital of XuzhouXuzhouPeople’s Republic of China
  4. 4.Department of RespiratoryThe First People’s Hospital of XuzhouXuzhouPeople’s Republic of China

Personalised recommendations