Interleukin-6: a potent biomarker of mycobacterial infection

SpringerPlus - Tập 2 - Trang 1-8 - 2013
Prati Pal Singh1, Amit Goyal1
1Centre of Infectious Diseases, Department of Pharmacology and Toxicology, National, Institute of Pharmaceutical Education and Research, India

Tóm tắt

Human tuberculosis (TB), a chronic inflammatory disease is caused by Mycobacterium tuberculosis, a facultative intramacrophage pathogen. The highly complex interactions between mycobacteria and macrophages (MΦs), characterized in part by the induction and elaboration of several cytokines including IL-1, IL-6, IL-10, IL-12 p40 and IL-12 p70 are not yet fully understood. The cytokines are known to have important bearing on the pathogenesis and host defense during TB. We thus studied different patterns of cytokines elaborated by mouse peritoneal macrophages (PMs) following their interaction with live and heat-killed, virulent and avirulent, and pathogenic and non-pathogenic mycobacteria, in vitro. Pathogenic M. tuberculosis H37Rv (virulent) and M. tuberculosis H37Ra (avirulent), and non-pathogenic M. smegmatis were grown in complete Middle Brook 7H9 broth. For some experiments, mycobacteria were heat-killed (80°C; 20 min). The supernatants of cultured PMs, having ingested mycobacteria for 6 h, 24 h, 4 days and 7 days, were harvested for the quantification of IL-1, IL-6, IL-10, IL-12 p40 and IL-12 p70 by using a multiplex suspension cytokine array system. The PMs infected with heat-killed mycobacteria, as compared to their respective live counterparts, invariably elaborated significantly (p < 0.001) increased (approximately 2–3-fold) amounts of IL-6, at all the time-points studied, in vitro. Further, PMs infected with M. tuberculosis H37Ra, as compared to M. tuberculosis H37Rv, elaborated 4–5-fold more (p < 0.001) IL-6. Non-pathogenic M. smegmatis, as compared to pathogenic M. tuberculosis H37Ra and M. tuberculosis H37Rv, following infection, induced the PMs to elaborate highest (p < 0.001) amounts of IL-6 at all the time-points studied. Curiously, none of these mycobacteria-infected PMs elaborated IL-1, IL-10, IL-12 p40 and IL-12 p70, significantly. IL-6 appears to be the only major cytokine elaborated by mycobacteria-infected PMs, in vitro, and thus may function as a potent biomarker of mycobacterial infection, either stand-alone or along with other cytokines.

Tài liệu tham khảo

Barker LP, George KM, Falkow S, Small PL: Differential trafficking of live and dead Mycobacterium marinum organisms in macrophages. Infect Immun 1997, 65: 1497-1504. Beltan E, Horgen L, Rastogi N: Secretion of cytokines by human macrophages upon infection by pathogenic and non-pathogenic mycobacteria. Microb Pathog 2000, 28: 313-318. 10.1006/mpat.1999.0345 Ben-Selma W, Harizi H, Boukadida J: Association of TNF-α and IL-10 polymorphisms with tuberculosis in Tunisian populations. Microbes Infect 2011, 13: 837-843. 10.1016/j.micinf.2011.04.009 Blanchard DK, Michelini-Norris MB, Pearson CA, Freitag CS, Djeu JY: Mycobacterium avium-intracellulare induces interleukin-6 from human monocytes and large granular lymphocytes. Blood 1991, 77: 2218-2224. Chatterjee D, Roberts A, Lowell K, Brennan P, Orme I: Structural basis of capacity of lipoarabinomannan to induce secretion of tumor necrosis factor. Infect Immun 1992, 60: 1249-1253. Cooper AM, Magram J, Ferrante J, Orme IM: Interleukin 12 (IL-12) is crucial to the development of protective immunity in mice intravenously infected with Mycobacterium tuberculosis . J Exp Med 1997, 186: 39-45. 10.1084/jem.186.1.39 Denis M: Interleukin-6 is used as a growth factor by virulent Mycobacterium avium : presence of specific receptors. Cell Immunol 1992, 141: 182-188. 10.1016/0008-8749(92)90137-E Dinarello CA: Biologic basis for interleukin-1 in disease. Blood 1996, 87: 2095-2147. Doherty M, Wallis RS, Zumla A: Biomarkers for tuberculosis disease status and diagnosis. Curr Opin Pulm Med 2009, 15: 181-187. 10.1097/MCP.0b013e328326f42c El-Ahmady O, Mansour M, Zoeir H, Mansour O: Elevated concentrations of interleukins and leukotriene in response to Mycobacterium tuberculosis infection. Ann Clin Biochem 1997, 34: 160-164. Elías-López AL, Marquina B, Gutiérrez-Ortega A, Aguilar D, Gomez-Lim M, Hernandez-Pando R: Transgenic tomato expressing interleukin-12 has a therapeutic effect in a murine model of progressive pulmonary tuberculosis. Clin Exp Immunol 2008, 154: 123-133. 10.1111/j.1365-2249.2008.03723.x Falcone V, Bassey EB, Toniolo A, Conaldi PG, Collins FM: Differential release of tumor necrosis factor-[alpha] from murine peritoneal macrophages stimulated with virulent and avirulent species of mycobacteria. FEMS Immunol Med Microbiol 1994, 8: 225-232. Feng CG, Kullberg MC, Jankovic D, Cheever AW, Caspar P, Coffmann RL, Sher A: Transgenic mice expressing human interleukin-10 in the antigen-presenting cell compartment show increased susceptibility to infection with Mycobacterium avium associated with decreased macrophage effector function and apoptosis. Infect Immun 2002, 70: 6672-6679. 10.1128/IAI.70.12.6672-6679.2002 Gordon A, Hart P, Young M: Ammonia inhibits phagosome-lysosome fusion in macrophages. Nature 1980, 286: 79-80. 10.1038/286079a0 Juffermans NP, Florquin S, Camoglio L, Verbon A, Kolk AH, Speelman P, Van Deventer SJH, Vander PT: Interleukin-1 signaling is essential for host defense during murine pulmonary tuberculosis. J Infect Dis 2000, 182: 902-908. 10.1086/315771 Kaur S, Kaur H, Singh PP: Induction of colony-stimulating factors by a 30-kDa secretory protein of Mycobacterium tuberculosis H37Rv. Eur Cytokine Netw 2004, 15: 327-338. Ladel CH, Blum C, Dreher A, Reifenberg K, Kopf M, Kaufmann SHE: Lethal tuberculosis in interleukin-6-deficient mutant mice. Infect Immun 1997, 65: 4843-4849. Leal IS, Florido M, Andersen P, Appelberg R: Interleukin-6 regulates the phenotype of the immune response to a tuberculosis subunit vaccine. Immunology 2001, 103: 375-381. 10.1046/j.1365-2567.2001.01244.x Mattos AMM, Almeida CDS, Franken KL, Alves CCDS, Abramo C, de Souza MA, L’Hotellier M, Alves MJ, Ferreira AP, Oliveira SC: Increased IgG1, IFN-γ, TNF-α and IL-6 responses to Mycobacterium tuberculosis antigens in patients with tuberculosis are lower after chemotherapy. Int Immunol 2010, 22: 775-782. 10.1093/intimm/dxq429 Murray PJ, Young RA: Increased antimycobacterial immunity in interleukin-10-deficient mice. Infect Immun 1999, 67: 3087-3095. North RJ, Jung YJ: Immunity to tuberculosis. Annu Rev Immunol 2004, 22: 599-623. 10.1146/annurev.immunol.22.012703.104635 Parida SK, Kaufmann SH: The quest for biomarkers in tuberculosis. Drug Discov Today 2010, 15: 148-157. 10.1016/j.drudis.2009.10.005 Redford PS, Murray PJ, O’Garra A: The role of IL-10 in immune regulation during M. tuberculosis infection. Mucosal Immunol 2011, 4: 261-270. 10.1038/mi.2011.7 Rhodes SG, Sawyer J, Whelan AO, Dean GS, Coad M, Ewer KJ, Waldvogel AS, Zakher A, Clifford DJ, Hewinson RG: Is interleukin-4δ3 splice variant expression in bovine tuberculosis a marker of protective immunity? Infect Immun 2007, 75: 3006-3013. 10.1128/IAI.01932-06 Saleh MT, Belisle JT: Secretion of an acid phosphatase (SapM) by Mycobacterium tuberculosis that is similar to eukaryotic acid phosphatases. J Bacteriol 2000, 182: 6850-6853. 10.1128/JB.182.23.6850-6853.2000 Saunders BM, Frank AA, Orme IM, Cooper AM: Interleukin-6 induces early gamma interferon production in the infected lung but is not required for generation of specific immunity to Mycobacterium tuberculosis infection. Infect Immun 2000, 68: 3322-3326. 10.1128/IAI.68.6.3322-3326.2000 Schindler R, Mancilla J, Endres S, Ghorbani R, Clark SC, Dinarello CA: Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF. Blood 1990, 75: 40-47. Shah NS, Wright A, Bai GH, Barrera L, Boulahbal F, Casabona NM, Drobniewski F, Gilpin C, Havelkova M, Lepe R, Lumb R, Metchok B, Portaels F, Rodrigues MF, Rusch-Gerdes S, Deun AV, Vincent V, Laserson K, Wells C, Cegielski JP: Worldwide emergence of extensively drug-resistant tuberculosis. Emerg Infect Dis 2007, 13: 380-387. 10.3201/eid1303.061400 Shiratsuchi H, Johnson JL, Ellner JJ: Bidirectional effects of cytokines on the growth of Mycobacterium avium within human monocytes. J Immunol 1991, 146: 3165-3170. Siawaya JFD, Bapela NB, Ronacher K, Beyers N, Van Helden P, Walzl G: Differential expression of interleukin-4 (IL-4) and IL-4δ2 mRNA, but not transforming growth factor beta (TGF-β), TGF-βRII, Foxp3, gamma interferon, T-bet, or GATA-3 mRNA, in patients with fast and slow responses to antituberculosis treatment. Clin Vaccine Immunol 2008, 15: 1165-1170. 10.1128/CVI.00084-08 Singh PP, Kaur S: Acute-phase reactants during murine tuberculosis: unknown dimensions and new frontiers. Tuberculosis 2005, 85: 303-315. 10.1016/j.tube.2005.08.002 Singh PP, Kaur S: Serum amyloid P-component in murine tuberculosis: induction kinetics and intramacrophage Mycobacterium tuberculosis growth inhibition in vitro . Microbes Infect 2006, 8: 541-551. 10.1016/j.micinf.2005.08.007 Tabarsi P, Marjani M, Mansouri N, Farnia P, Boisson-Dupuis S, Bustamante J, Abel L, Adimi P, Casanova JL, Mansouri D: Lethal tuberculosis in a previously healthy adult with IL-12 receptor deficiency. J Clin Immunol 2011, 31: 537-539. 10.1007/s10875-011-9523-9 Trinchieri G: Interleukin-12: a pro-inflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu Rev Immunol 1995, 13: 251-276. 10.1146/annurev.iy.13.040195.001343 Van Snick J: Interleukin-6: an overview. Annu Rev Immunol 1990, 8: 253-278. 10.1146/annurev.iy.08.040190.001345 Vergne I, Chua J, Lee HH, Lucas M, Belisle J, Deretic V: Mechanism of phagolysosome biogenesis block by viable Mycobacterium tuberculosis . Proc Natl Acad Sci U S A 2005, 102: 4033-4038. 10.1073/pnas.0409716102 Wassie L, Demissie A, Aseffa A, Abebe M, Yamuah L, Tilahun H, Petros B, Rook G, Zumla A, Andersen P: Ex vivo cytokine mRNA levels correlate with changing clinical status of Ethiopian TB patients and their contacts over time. PLoS One 2008, 3: e1522. 10.1371/journal.pone.0001522 World Health Organization: Global tuberculosis control. World Health Organization, Geneva, Switzerland; 2012. Yamada H, Mizumo S, Horai R, Iwakura Y, Sugawara I: Protective role of interleukin-1 in mycobacterial infection in IL-1 α/β double-knockout mice. Lab Invest 2000, 80: 759-767. 10.1038/labinvest.3780079 Zhang Y, Broser M, Rom WN: Activation of the interleukin 6 gene by Mycobacterium tuberculosis or lipopolysaccharide is mediated by nuclear factors NF-IL6 and NF-kappa B. Proc Natl Acad Sci U S A 1994, 91: 2225-2229. 10.1073/pnas.91.6.2225