IMMUNE NETWORK

The Korean Association of Immunobiologists (대한면역학회)
권호 표지
DOI QR코드

DOI QR Code

Mycobacterial Heparin-binding Hemagglutinin Antigen Activates Inflammatory Responses through PI3-K/Akt, NF-${\kappa}B$, and MAPK Pathways

  • Kim, Ki-Hye (Department of Microbiology, College of Medicine, Chungnam National University) ;
  • Yang, Chul-Su (Department of Microbiology, College of Medicine, Chungnam National University) ;
  • Shin, A-Rum (Department of Microbiology, College of Medicine, Chungnam National University) ;
  • Jeon, So-Ra (Department of Microbiology, College of Medicine, Chungnam National University) ;
  • Park, Jeong-Kyu (Department of Microbiology, College of Medicine, Chungnam National University) ;
  • Kim, Hwa-Jung (Department of Microbiology, College of Medicine, Chungnam National University) ;
  • Jo, Eun-Kyeong (Department of Microbiology, College of Medicine, Chungnam National University)
  • Received : 2011.03.18
  • Accepted : 2011.04.14
  • Published : 2011.04.30
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Mycobacterium tuberculosis (Mtb) heparin binding hemagglutinin (HBHA) is an Ag known to evoke effective host immune responses during tuberculosis infection. However, the molecular basis of the host immune response to HBHA has not been fully characterized. In this study, we examined the molecular mechanisms by which HBHA can induce the expression of proinflammatory cytokines in macrophages. Methods: HBHA-induced mRNA and protein levels of proinflammatory cytokines were determined in bone marrow-derived macrophages (BMDMs) using RT-PCR and ELISA analysis. The roles of intracellular signaling pathways for NF-${\kappa}B$, PI3-K/Akt, and MAPKs were investigated in macrophage proinflammatory responses after stimulation with HBHA. Results: HBHA robustly activated the expression of mRNA and protein of both TNF-${\alpha}$ and IL-6, and induced phosphorylation of NF-${\kappa}B$, Akt, and MAPKs in BMDMs. Both TNF-${\alpha}$ and IL-6 production by HBHA was regulated by the NF-${\kappa}B$, PI3-K, and MAPK pathways. Furthermore, PI3-K activity was required for the HBHA-induced activation of ERK1/2 and p38 MAPK, but not JNK, pathways. Conclusion: These data suggest that mycobacterial HBHA significantly induces proinflammatory responses through crosstalk between the PI3-K and MAPK pathways in macrophages.

Keywords

References

  1. Jo EK, Yang CS, Choi CH, Harding CV: Intracellular signalling cascades regulating innate immune responses to Mycobacteria: branching out from Toll-like receptors. Cell Microbiol 9;1087-1098, 2007 https://doi.org/10.1111/j.1462-5822.2007.00914.x
  2. Menozzi FD, Bischoff R, Fort E, Brennan MJ, Locht C: Molecular characterization of the mycobacterial heparin-binding hemagglutinin, a mycobacterial adhesin. Proc Natl Acad Sci U S A 95;12625-12630, 1998 https://doi.org/10.1073/pnas.95.21.12625
  3. Pethe K, Bifani P, Drobecq H, Sergheraert C, Debrie AS, Locht C, Menozzi FD: Mycobacterial heparin-binding hemagglutinin and laminin-binding protein share antigenic methyllysines that confer resistance to proteolysis. Proc Natl Acad Sci U S A 99;10759-10764, 2002 https://doi.org/10.1073/pnas.162246899
  4. Menozzi FD, Rouse JH, Alavi M, Laude-Sharp M, Muller J, Bischoff R, Brennan MJ, Locht C: Identification of a heparin-binding hemagglutinin present in mycobacteria. J Exp Med 184;993-1001, 1996 https://doi.org/10.1084/jem.184.3.993
  5. Parra M, Pickett T, Delogu G, Dheenadhayalan V, Debrie AS, Locht C, Brennan MJ: The mycobacterial heparin-binding hemagglutinin is a protective antigen in the mouse aerosol challenge model of tuberculosis. Infect Immun 72;6799-6805, 2004 https://doi.org/10.1128/IAI.72.12.6799-6805.2004
  6. Korbel DS, Schneider BE, Schaible UE: Innate immunity in tuberculosis: myths and truth. Microbes Infect 10;995-1004, 2008 https://doi.org/10.1016/j.micinf.2008.07.039
  7. Brightbill HD, Libraty DH, Krutzik SR, Yang RB, Belisle JT, Bleharski JR, Maitland M, Norgard MV, Plevy SE, Smale ST, Brennan PJ, Bloom BR, Godowski PJ, Modlin RL: Host defense mechanisms triggered by microbial lipoproteins through toll-like receptors. Science 285;732-736, 1999 https://doi.org/10.1126/science.285.5428.732
  8. Toossi Z: Cytokine circuits in tuberculosis. Infect Agents Dis 5;98-107, 1996
  9. Bermudez LE, Young LS: Tumor necrosis factor, alone or in combination with IL-2, but not IFN-gamma, is associated with macrophage killing of Mycobacterium avium complex. J Immunol 140;3006-3013, 1988
  10. Lee JS, Song CH, Lim JH, Kim HJ, Park JK, Paik TH, Kim CH, Kong SJ, Shon MH, Jung SS, Jo EK: The production of tumour necrosis factor-alpha is decreased in peripheral blood mononuclear cells from multidrug-resistant tuberculosis patients following stimulation with the 30-kDa antigen of Mycobacterium tuberculosis. Clin Exp Immunol 132;443-449, 2003 https://doi.org/10.1046/j.1365-2249.2003.02172.x
  11. Jung SB, Yang CS, Lee JS, Shin AR, Jung SS, Son JW, Harding CV, Kim HJ, Park JK, Paik TH, Song CH, Jo EK: The mycobacterial 38-kilodalton glycolipoprotein antigen activates the mitogen-activated protein kinase pathway and release of proinflammatory cytokines through Toll-like receptors 2 and 4 in human monocytes. Infect Immun 74; 2686-2696, 2006 https://doi.org/10.1128/IAI.74.5.2686-2696.2006
  12. Yang CS, Shin DM, Lee HM, Son JW, Lee SJ, Akira S, Gougerot-Pocidalo MA, El-Benna J, Ichijo H, Jo EK: ASK1-p38 MAPK-p47phox activation is essential for inflammatory responses during tuberculosis via TLR2-ROS signalling. Cell Microbiol 10;741-754, 2008 https://doi.org/10.1111/j.1462-5822.2007.01081.x
  13. Aleman M, Schierloh P, de la Barrera SS, Musella RM, Saab MA, Baldini M, Abbate E, Sasiain MC: Mycobacterium tuberculosis triggers apoptosis in peripheral neutrophils involving toll-like receptor 2 and p38 mitogen protein kinase in tuberculosis patients. Infect Immun 72;5150-5158, 2004 https://doi.org/10.1128/IAI.72.9.5150-5158.2004
  14. Delogu G, Bua A, Pusceddu C, Parra M, Fadda G, Brennan MJ, Zanetti S: Expression and purification of recombinant methylated HBHA in Mycobacterium smegmatis. FEMS Microbiol Lett 239;33-39, 2004 https://doi.org/10.1016/j.femsle.2004.08.015
  15. Shin AR, Lee KS, Lee JS, Kim SY, Song CH, Jung SB, Yang CS, Jo EK, Park JK, Paik TH, Kim HJ: Mycobacterium tuberculosis HBHA protein reacts strongly with the serum immunoglobulin M of tuberculosis patients. Clin Vaccine Immunol 13;869-875, 2006 https://doi.org/10.1128/CVI.00103-06
  16. Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol 12;141-179, 1994 https://doi.org/10.1146/annurev.iy.12.040194.001041
  17. Pathak SK, Bhattacharyya A, Pathak S, Basak C, Mandal D, Kundu M, Basu J: Toll-like receptor 2 and mitogen- and stress-activated kinase 1 are effectors of Mycobacterium avium-induced cyclooxygenase-2 expression in macrophages. J Biol Chem 279;55127-55136, 2004 https://doi.org/10.1074/jbc.M409885200
  18. Yadav M, Roach SK, Schorey JS: Increased mitogen-activated protein kinase activity and TNF-alpha production associated with Mycobacterium smegmatis- but not Mycobacterium avium-infected macrophages requires prolonged stimulation of the calmodulin/calmodulin kinase and cyclic AMP/protein kinase A pathways. J Immunol 172;5588-5597, 2004
  19. Lee HM, Shin DM, Kim KK, Lee JS, Paik TH, Jo EK: Roles of reactive oxygen species in CXCL8 and CCL2 expression in response to the 30-kDa antigen of Mycobacterium tuberculosis. J Clin Immunol 29;46-56, 2009 https://doi.org/10.1007/s10875-008-9222-3
  20. Jung SB, Song CH, Yang CS, Kim SY, Lee KS, Shin AR, Lee JS, Nam HS, Kim HJ, Park JK, Paik TH, Jo EK: Role of the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways in the secretion of tumor necrosis factor-alpha and interleukin-10 by the PPD antigen of Mycobacterium tuberculosis. J Clin Immunol 25;482-490, 2005 https://doi.org/10.1007/s10875-005-5431-1
  21. Schorey JS, Cooper AM: Macrophage signalling upon mycobacterial infection: the MAP kinases lead the way. Cell Microbiol 5;133-142, 2003 https://doi.org/10.1046/j.1462-5822.2003.00263.x
  22. Darieva Z, Lasunskaia EB, Campos MN, Kipnis TL, Da Silva WD: Activation of phosphatidylinositol 3-kinase and c-Jun-N-terminal kinase cascades enhances NF-kappaB-dependent gene transcription in BCG-stimulated macrophages through promotion of p65/p300 binding. J Leukoc Biol 75;689-697, 2004 https://doi.org/10.1189/jlb.0603280
  23. Sendide K, Reiner NE, Lee JS, Bourgoin S, Talal A, Hmama Z: Cross-talk between CD14 and complement receptor 3 promotes phagocytosis of mycobacteria: regulation by phosphatidylinositol 3-kinase and cytohesin-1. J Immunol 174;4210-4219, 2005 https://doi.org/10.4049/jimmunol.174.7.4210
  24. Yang CS, Lee JS, Jung SB, Oh JH, Song CH, Kim HJ, Park JK, Paik TH, Jo EK: Differential regulation of interleukin-12 and tumour necrosis factor-alpha by phosphatidylinositol 3-kinase and ERK 1/2 pathways during Mycobacterium tuberculosis infection. Clin Exp Immunol 143;150-160, 2006 https://doi.org/10.1111/j.1365-2249.2005.02966.x
  25. Weir RE, Black GF, Dockrell HM, Floyd S, Fine PE, Chaguluka SD, Stenson S, King E, Nazareth B, Warndorff DK, Ngwira B, Crampin AC, Mwaungulu L, Sichali L, Jarman E, Donovan L, Blackwell JM: Mycobacterial purified protein derivatives stimulate innate immunity: Malawians show enhanced tumor necrosis factor alpha, interleukin- 1beta (IL-1beta), and IL-10 responses compared to those of adolescents in the United Kingdom. Infect Immun 72;1807-1811, 2004 https://doi.org/10.1128/IAI.72.3.1807-1811.2004
  26. Wallis RS, Amir-Tahmasseb M, Ellner JJ: Induction of interleukin 1 and tumor necrosis factor by mycobacterial proteins: the monocyte western blot. Proc Natl Acad Sci U S A 87;3348-3352, 1990 https://doi.org/10.1073/pnas.87.9.3348
  27. Temmerman S, Pethe K, Parra M, Alonso S, Rouanet C, Pickett T, Drowart A, Debrie AS, Delogu G, Menozzi FD, Sergheraert C, Brennan MJ, Mascart F, Locht C: Methylationdependent T cell immunity to Mycobacterium tuberculosis heparin-binding hemagglutinin. Nat Med 10;935-941, 2004 https://doi.org/10.1038/nm1090
  28. Hougardy JM, Schepers K, Place S, Drowart A, Lechevin V, Verscheure V, Debrie AS, Doherty TM, Van Vooren JP, Locht C, Mascart F: Heparin-binding-hemagglutinin-induced IFN-gamma release as a diagnostic tool for latent tuberculosis. PLoS One 2;e926, 2007 https://doi.org/10.1371/journal.pone.0000926
  29. Locht C, Hougardy JM, Rouanet C, Place S, Mascart F: Heparin-binding hemagglutinin, from an extrapulmonary dissemination factor to a powerful diagnostic and protective antigen against tuberculosis. Tuberculosis (Edinb) 86;303-309, 2006 https://doi.org/10.1016/j.tube.2006.01.016
  30. Roach DR, Briscoe H, Saunders B, France MP, Riminton S, Britton WJ: Secreted lymphotoxin-alpha is essential for the control of an intracellular bacterial infection. J Exp Med 193;239-246, 2001 https://doi.org/10.1084/jem.193.2.239
  31. Ghosh S, Hayden MS: New regulators of NF-kappaB in inflammation. Nat Rev Immunol 8;837-848, 2008 https://doi.org/10.1038/nri2423
  32. Wang T, Lafuse WP, Zwilling BS: NFkappaB and Sp1 elements are necessary for maximal transcription of toll-like receptor 2 induced by Mycobacterium avium. J Immunol 167;6924-6932, 2001 https://doi.org/10.4049/jimmunol.167.12.6924
  33. Bulut Y, Michelsen KS, Hayrapetian L, Naiki Y, Spallek R, Singh M, Arditi M: Mycobacterium tuberculosis heat shock proteins use diverse Toll-like receptor pathways to activate pro-inflammatory signals. J Biol Chem 280;20961-20967, 2005 https://doi.org/10.1074/jbc.M411379200
  34. Thoma-Uszynski S, Stenger S, Takeuchi O, Ochoa MT, Engele M, Sieling PA, Barnes PF, Rollinghoff M, Bolcskei PL, Wagner M, Akira S, Norgard MV, Belisle JT, Godowski PJ, Bloom BR, Modlin RL: Induction of direct antimicrobial activity through mammalian toll-like receptors. Science 291;1544-1547, 2001 https://doi.org/10.1126/science.291.5508.1544
  35. Maiti D, Bhattacharyya A, Basu J: Lipoarabinomannan from Mycobacterium tuberculosis promotes macrophage survival by phosphorylating Bad through a phosphatidylinositol 3-kinase/Akt pathway. J Biol Chem 276;329-333, 2001 https://doi.org/10.1074/jbc.M002650200
  36. Vanhaesebroeck B, Jones GE, Allen WE, Zicha D, Hooshmand-Rad R, Sawyer C, Wells C, Waterfield MD, Ridley AJ: Distinct PI(3)Ks mediate mitogenic signalling and cell migration in macrophages. Nat Cell Biol 1;69-71, 1999 https://doi.org/10.1038/9045
  37. Sly LM, Lopez M, Nauseef WM, Reiner NE: 1alpha, 25-Dihydroxyvitamin D3-induced monocyte antimycobacterial activity is regulated by phosphatidylinositol 3-kinase and mediated by the NADPH-dependent phagocyte oxidase. J Biol Chem 276;35482-35493, 2001 https://doi.org/10.1074/jbc.M102876200
  38. Lee JS, Son JW, Jung SB, Kwon YM, Yang CS, Oh JH, Song CH, Kim HJ, Park JK, Paik TH, Jo EK: Ex vivo responses for interferon-gamma and proinflammatory cytokine secretion to low-molecular-weight antigen MTB12 of Mycobacterium tuberculosis during human tuberculosis. Scand J Immunol 64;145-154, 2006 https://doi.org/10.1111/j.1365-3083.2006.01784.x
  39. Song CH, Lee JS, Lee SH, Lim K, Kim HJ, Park JK, Paik TH, Jo EK: Role of mitogen-activated protein kinase pathways in the production of tumor necrosis factor-alpha, interleukin-10, and monocyte chemotactic protein-1 by Mycobacterium tuberculosis H37Rv-infected human monocytes. J Clin Immunol 23;194-201, 2003 https://doi.org/10.1023/A:1023309928879
  40. Rajaram MV, Ganesan LP, Parsa KV, Butchar JP, Gunn JS, Tridandapani S: Akt/Protein kinase B modulates macrophage inflammatory response to Francisella infection and confers a survival advantage in mice. J Immunol 177;6317-6324, 2006 https://doi.org/10.4049/jimmunol.177.9.6317
  41. Guha M, Mackman N: The phosphatidylinositol 3-kinase-Akt pathway limits lipopolysaccharide activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. J Biol Chem 277;32124-32132, 2002 https://doi.org/10.1074/jbc.M203298200
  42. Zhang WJ, Wei H, Hagen T, Frei B: Alpha-lipoic acid attenuates LPS-induced inflammatory responses by activating the phosphoinositide 3-kinase/Akt signaling pathway. Proc Natl Acad Sci U S A 104;4077-4082, 2007 https://doi.org/10.1073/pnas.0700305104
  43. Hawes BE, Luttrell LM, van Biesen T, Lefkowitz RJ: Phosphatidylinositol 3-kinase is an early intermediate in the G beta gamma-mediated mitogen-activated protein kinase signaling pathway. J Biol Chem 271;12133-12136, 1996 https://doi.org/10.1074/jbc.271.21.12133
  44. Jung ID, Jeong SK, Lee CM, Noh KT, Heo DR, Shin YK, Yun CH, Koh WJ, Akira S, Whang J, Kim HJ, Park WS, Shin SJ, Park YM: Enhanced Efficacy of Therapeutic Cancer Vaccines Produced by Co-Treatment with Mycobacterium tuberculosis Heparin-Binding Hemagglutinin, a Novel TLR4 Agonist. Cancer Res 71;2858-2870, 2011 https://doi.org/10.1158/0008-5472.CAN-10-3487
  45. Place S, Verscheure V, de San N, Hougardy JM, Schepers K, Dirix V, Dediste A, Michel O, Drowart A, Allard SD, Doherty TM, Lecher S, Locht C, Mascart F: Heparin-binding, hemagglutinin-specific IFN-gamma synthesis at the site of infection during active tuberculosis in humans. Am J Respir Crit Care Med 182;848-854, 2010 https://doi.org/10.1164/rccm.201001-0083OC
  46. Zanetti S, Bua A, Delogu G, Pusceddu C, Mura M, Saba F, Pirina P, Garzelli C, Vertuccio C, Sechi LA, Fadda G: Patients with pulmonary tuberculosis develop a strong humoral response against methylated heparin-binding hemagglutinin. Clin Diagn Lab Immunol 12;1135-1138, 2005

Cited by

  1. Radiation-induced angiogenic signaling pathway in endothelial cells obtained from normal and cancer tissue of human breast vol.33, pp.10, 2011, https://doi.org/10.1038/onc.2013.70
  2. Mycobacterium tuberculosis Rv2882c Protein Induces Activation of Macrophages through TLR4 and Exhibits Vaccine Potential vol.11, pp.10, 2016, https://doi.org/10.1371/journal.pone.0164458
  3. Guanine nucleotide exchange factor -H1 promotes inflammatory cytokine production and intracellular mycobacterial elimination in macrophages vol.16, pp.18, 2011, https://doi.org/10.1080/15384101.2017.1347739
  4. Involvement of the PI3K/Akt/NF- κ B Signaling Pathway in the Attenuation of Severe Acute Pancreatitis-Associated Acute Lung Injury by Sedum sarmentosum Bunge Extract vol.2017, pp.None, 2011, https://doi.org/10.1155/2017/9698410
  5. Mycobacterium tuberculosis Peptidyl-Prolyl Isomerases Are Immunogenic, Alter Cytokine Profile and Aid in Intracellular Survival vol.7, pp.None, 2011, https://doi.org/10.3389/fcimb.2017.00038
  6. Interaction of the CD43 Sialomucin with the Mycobacterium tuberculosis Cpn60.2 Chaperonin Leads to Tumor Necrosis Factor Alpha Production vol.85, pp.3, 2011, https://doi.org/10.1128/iai.00915-16
  7. Co-Expression of hbha and mtb32C Genes from Mycobacterium tuberculosis H37Rv in a Prokaryotic System vol.11, pp.2, 2011, https://doi.org/10.5812/jjm.14030
  8. Rv2346c enhances mycobacterial survival within macrophages by inhibiting TNF-α and IL-6 production via the p38/miRNA/NF-κB pathway vol.7, pp.1, 2011, https://doi.org/10.1038/s41426-018-0162-6
  9. Bioinformatics analysis of microRNA expression between patients with and without latent tuberculosis infections vol.17, pp.5, 2011, https://doi.org/10.3892/etm.2019.7424
  10. The Heparin-Binding Hemagglutinin of Nocardia cyriacigeorgica GUH-2 Stimulates Inflammatory Cytokine Secretion Through Activation of Nuclear Factor κB and Mitogen-Activated Protein Kinase Path vol.10, pp.None, 2020, https://doi.org/10.3389/fcimb.2020.00003
  11. BCG Cell Wall Skeleton As a Vaccine Adjuvant Protects Both Infant and Old-Aged Mice from Influenza Virus Infection vol.9, pp.5, 2021, https://doi.org/10.3390/biomedicines9050516
  12. The regulate function of polysaccharides and oligosaccharides that with sulfate group on immune-related disease vol.88, pp.None, 2011, https://doi.org/10.1016/j.jff.2021.104870