The resistance of epithelial cells infected with Chlamydophila pneumoniae for apoptosis has been attributed to the induced expression and increased stability of anti-apoptotic proteins called inhibitor of apoptosis proteins (IAPs). The significance of cellular inhibitor of apoptosis protein-1 (cIAP-1) in C. pneumoniae pulmonary infection and innate immune response was investigated in cIAP-1 knockout (KO) mice using a novel non-invasive intra-tracheal infection method. In contrast to wildtype, cIAP-1 knockout mice failed to clear the infection from their lungs. Wildtype mice responded to infection with a strong inflammatory response in the lung. In contrast, the recruitment of macrophages was reduced in cIAP-1 KO mice compared to wildtype mice. The concentration of Interferon gamma (IFN-γ) was increased whereas that of Tumor Necrosis Factor (TNF-α) was reduced in the lungs of infected cIAP-1 KO mice compared to infected wildtype mice. Ex vivo experiments on mouse peritoneal macrophages and splenocytes revealed that cIAP-1 is required for innate immune responses of these cells. Our findings thus suggest a new immunoregulatory role of cIAP-1 in the course of bacterial infection.
Molestina RE, Miller RD, Ramirez JA, Summersgill JT (1999) Infection of human endothelial cells with Chlamydia pneumoniae stimulates transendothelial migration of neutrophils and monocytes. Infect Immun 67: 1323–1330.
[3]
Gaydos CA, Summersgill JT, Sahney NN, Ramirez JA, Quinn TC (1996) Replication of Chlamydia pneumoniae in vitro in human macrophages, endothelial cells, and aortic artery smooth muscle cells. Infect Immun 64: 1614–1620.
[4]
Heinemann M, Susa M, Simnacher U, Marre R, Essig A (1996) Growth of Chlamydia pneumoniae induces cytokine production and expression of CD14 in a human monocytic cell line. Infect Immun 64: 4872–4875.
[5]
Airenne S, Surcel HM, Alakarppa H, Laitinen K, Paavonen J, et al. (1999) Chlamydia pneumoniae infection in human monocytes. Infect Immun 67: 1445–1449.
[6]
Cochrane M, Pospischil A, Walker P, Gibbs H, Timms P (2005) Discordant detection of Chlamydia pneumoniae in patients with carotid artery disease using polymerase chain reaction, immunofluorescence microscopy and serological methods. Pathology 37: 69–75.
Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20: 197–216.
[9]
Matzinger P (2002) The danger model: a renewed sense of self. Science 296: 301–305.
[10]
Topley N, Mackenzie RK, Williams JD (1996) Macrophages and mesothelial cells in bacterial peritonitis. Immunobiology 195: 563–573.
[11]
Fan T, Lu H, Hu H, Shi L, McClarty GA, et al. (1998) Inhibition of apoptosis in chlamydia-infected cells: blockade of mitochondrial cytochrome c release and caspase activation. J Exp Med 187: 487–496.
[12]
Rajalingam K, Al Younes H, Muller A, Meyer TF, Szczepek AJ, et al. (2001) Epithelial cells infected with Chlamydophila pneumoniae (Chlamydia pneumoniae) are resistant to apoptosis. Infect Immun 69: 7880–7888.
[13]
Fischer SF, Schwarz C, Vier J, Hacker G (2001) Characterization of Antiapoptotic Activities of Chlamydia pneumoniae in Human Cells. Infect Immun 69: 7121–7129.
[14]
Paland N, Rajalingam K, Machuy N, Szczepek A, Wehrl W, et al. (2006) NF-kappaB and inhibitor of apoptosis proteins are required for apoptosis resistance of epithelial cells persistently infected with Chlamydophila pneumoniae. Cell Microbiol 8: 1643–1655.
[15]
Rajalingam K, Sharma M, Paland N, Hurwitz R, Thieck O, et al. (2006) IAP-IAP Complexes Required for Apoptosis Resistance of C. trachomatis–Infected Cells. PLoS Pathogens 2: e114.
[16]
Miller LK (1999) An exegesis of IAPs: salvation and surprises from BIR motifs. Trends Cell Biol 9: 323–328.
[17]
Roy N, Deveraux QL, Takahashi R, Salvesen GS, Reed JC (1997) The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. EMBO J 16: 6914–6925.
[18]
Deveraux QL, Takahashi R, Salvesen GS, Reed JC (1997) X-linked IAP is a direct inhibitor of cell-death proteases. Nature 388: 300–304.
[19]
Eckelman BP, Salvesen GS, Scott FL (2006) Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep 7: 988–994.
Leulier F, Lhocine N, Lemaitre B, Meier P (2006) The Drosophila inhibitor of apoptosis protein DIAP2 functions in innate immunity and is essential to resist gram-negative bacterial infection. Mol Cell Biol 26: 7821–7831.
[22]
Shu HB, Takeuchi M, Goeddel DV (1996) The tumor necrosis factor receptor 2 signal transducers TRAF2 and c-IAP1 are components of the tumor necrosis factor receptor 1 signaling complex. Proc Natl Acad Sci U S A 93: 13973–13978.
[23]
Chan KF, Siegel MR, Lenardo JM (2000) Signaling by the TNF receptor superfamily and T cell homeostasis. Immunity 13: 419–422.
[24]
Conte D, Holcik M, Lefebvre CA, Lacasse E, Picketts DJ, et al. (2006) Inhibitor of apoptosis protein cIAP2 is essential for lipopolysaccharide-induced macrophage survival. Mol Cell Biol 26: 699–708.
Klimp AH, de Vries EG, Scherphof GL, Daemen T (2002) A potential role of macrophage activation in the treatment of cancer. Crit Rev Oncol Hematol 44: 143–161.
[27]
Bogdan C (2001) Nitric oxide and the immune response. Nat Immunol 2: 907–916.
[28]
Dockrell DH, Marriott HM, Prince LR, Ridger VC, Ince PG, et al. (2003) Alveolar macrophage apoptosis contributes to pneumococcal clearance in a resolving model of pulmonary infection. J Immunol 171: 5380–5388.
[29]
Mahoney DJ, Cheung HH, Mrad RL, Plenchette S, Simard C, et al. (2008) Both cIAP1 and cIAP2 regulate TNFalpha-mediated NF-kappaB activation. Proc Natl Acad Sci U S A 105: 11778–11783.
[30]
Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N, et al. (2007) IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell 131: 669–681.
[31]
Chu ZL, McKinsey TA, Liu L, Gentry JJ, Malim MH, et al. (1997) Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-kappaB control. Proc Natl Acad Sci U S A 94: 10057–10062.
[32]
Shu HB, Takeuchi M, Goeddel DV (1996) The tumor necrosis factor receptor 2 signal transducers TRAF2 and c-IAP1 are components of the tumor necrosis factor receptor 1 signaling complex. Proc Natl Acad Sci U S A 93: 13973–13978.
[33]
Conze DB, Albert L, Ferrick DA, Goeddel DV, Yeh WC, et al. (2005) Posttranscriptional downregulation of c-IAP2 by the ubiquitin protein ligase c-IAP1 in vivo. Mol Cell Biol 25: 3348–3356.
[34]
Rottenberg ME, Gigliotti-Rothfuchs A, Wigzell H (2002) The role of IFN-gamma in the outcome of chlamydial infection. Curr Opin Immunol 14: 444–451.
[35]
Costa CP, Kirschning CJ, Busch D, Durr S, Jennen L, et al. (2002) Role of chlamydial heat shock protein 60 in the stimulation of innate immune cells by Chlamydia pneumoniae. Eur J Immunol 32: 2460–2470.
[36]
Redecke V, Dalhoff K, Bohnet S, Braun J, Maass M (1998) Interaction of Chlamydia pneumoniae and human alveolar macrophages: infection and inflammatory response. Am J Respir Cell Mol Biol 19: 721–727.
[37]
Currier AR, Ziegler MH, Riley MM, Babcock TA, Telbis VP, et al. (2000) Tumor necrosis factor-alpha and lipopolysaccharide enhance interferon-induced antichlamydial indoleamine dioxygenase activity independently. Journal of Interferon and Cytokine Research 20: 369–376.
[38]
Haranaga S, Yamaguchi H, Ikejima H, Friedman H, Yamamoto Y (2003) Chlamydia pneumoniae infection of alveolar macrophages: a model. J Infect Dis 187: 1107–1115.
[39]
Chakravortty D, Hensel M (2003) Inducible nitric oxide synthase and control of intracellular bacterial pathogens. Microbes Infect 5: 621–627.
[40]
Chen BJ, Stout R, Campbell WF (1996) Nitric oxide production: A mechanism of Chlamydia trachomatis inhibition in interferon-gamma-treated RAW264.7 cells. Fems Immunology and Medical Microbiology 14: 109–120.
[41]
Carratelli CR, Rizzo A, Paolillo R, Catania MR, Catalanotti P, et al. (2005) Effect of nitric oxide on the growth of Chlamydophila pneumoniae. Canadian Journal of Microbiology 51: 941–947.
[42]
Dalton DK, Pitts-Meek S, Keshav S, Figari IS, Bradley A, et al. (1993) Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science 259: 1739–1742.
[43]
Kamijo R, Shapiro D, Le J, Huang S, Aguet M, et al. (1993) Generation of nitric oxide and induction of major histocompatibility complex class II antigen in macrophages from mice lacking the interferon gamma receptor. Proc Natl Acad Sci U S A 90: 6626–6630.
[44]
Meraz MA, White JM, Sheehan KC, Bach EA, Rodig SJ, et al. (1996) Targeted disruption of the Stat1 gene in mice reveals unexpected physiologic specificity in the JAK-STAT signaling pathway. Cell 84: 431–442.
[45]
Boise LH, Collins CM (2001) Salmonella-induced cell death: apoptosis, necrosis or programmed cell death? Trends Microbiol 9: 64–67.
[46]
Fink SL, Cookson BT (2007) Pyroptosis and host cell death responses during Salmonella infection. Cell Microbiol 9: 2562–2570.
[47]
Monack DM, Hersh D, Ghori N, Bouley D, Zychlinsky A, et al. (2000) Salmonella exploits caspase-1 to colonize Peyer's patches in a murine typhoid model. J Exp Med 192: 249–258.
[48]
Kilbourn RG, Gross SS, Jubran A, Adams J, Griffith OW, et al. (1990) NG-methyl-L-arginine inhibits tumor necrosis factor-induced hypotension: implications for the involvement of nitric oxide. Proc Natl Acad Sci U S A 87: 3629–3632.
[49]
Feihl F, Waeber B, Liaudet L (2001) Is nitric oxide overproduction the target of choice for the management of septic shock? Pharmacol Ther 91: 179–213.
[50]
Thiemermann C, McDonald MC, Cuzzocrea S (2001) The stable nitroxide, tempol, attenuates the effects of peroxynitrite and oxygen-derived free radicals. Crit Care Med 29: 223–224.
[51]
Chen W, Kuo C (1980) A mouse model of pneumonitis induced by Chlamydia trachomatis: morphologic, microbiologic, and immunologic studies. Am J Pathol 100: 365–382.
[52]
Paland N, Bohme L, Gurumurthy RK, Maurer A, Szczepek AJ, et al. (2008) Reduced display of tumor necrosis factor receptor I at the host cell surface supports infection with Chlamydia trachomatis. J Biol Chem 283: 6438–6448.
[53]
Ly IA, Mishell RI (1974) Separation of mouse spleen cells by passage through columns of sephadex G-10. J Immunol Methods 5: 239–247.
