Transcriptional Signaling Hubs in Epithelial Cells During Pneumonia

  • Lee J. Quinton
  • Joseph P. Mizgerd


The respiratory surface is composed of heterogeneous epithelial cells with diverse cell-specific functions (Franks et al. 2008). The epithelium constitutes a barrier between the ambient environment and the internal milieu, and as such the epithelial cells help protect the body from bacteria and other materials that are inhaled or aspirated into the air spaces of the lung. Epithelial cells have constitutive activities that are clearly essential to host defense, including the elaboration of a surface lining fluid with chemical and physical properties that enhance antibacterial defense. In the airways, the mucociliary escalator traps inhaled materials and propels them out of the lungs, transporting them up the airways and past the glottis until they become swallowed and eliminated. This defense is a product of the airway epithelium, including coordinated efforts of glandular, secretory, and ciliated cells. The common and severe lung infections in patients with genetic defects influencing mucociliary escalator function, such as primary ciliary dyskinesia (Bush et al. 2007) or cystic fibrosis (Boucher 2007), highlight the critical role of this constitutive host defense system. In the alveoli, the type II cells basally secrete the lipid and protein components of the surfactant lining fluid. The surfactant proteins A and D are collectins with diverse host defense roles against bacteria, and the significance of these constitutive defenses are highlighted by the susceptibility to lung infection of mice with genetic deficiencies of surfactant proteins A or D (Wright 2005). Thus, the epithelial cells of the lung constitutively function to protect the lung from bacterial infection. When bacteria are too numerous or too virulent to be eliminated by constitutive defenses, recruited innate immune defenses are needed. These innate immune responses involve the integrated functions of structural elements such as lung epithelial cells and immune cells such as macrophages and neutrophils. This chapter will focus on the innate immune responses of lung epithelial cells, including their molecular regulation and contributions to mucosal immunology and tissue homeostasis during acute bacterial pneumonia. Specifically, we will highlight knowledge about two transcription factor signaling hubs which appear to be especially important to epithelial responses during pneumonia, NF-κB, and STAT3.


Lung Injury Host Defense Airway Epithelial Cell Alveolar Epithelial Cell Lung Epithelial Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Akira S, Nishio Y, Inoue M, Wang XJ, Wei S, Matsusaka T, Yoshida K, Sudo T, Naruto M, Kishimoto T (1994) Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 77:63–71PubMedCrossRefGoogle Scholar
  2. Alcamo EA, Mizgerd JP, Horwitz BH, Bronson R, Beg AA, Scott M, Doerschuk CM, Hynes RO, Baltimore D (2001) Targeted mutation of tumor necrosis factor 1 rescues the RelA-deficient mouse and reveals a critical role for NF-κB in leukocyte recruitment. J Immunol 167:1592–1600PubMedGoogle Scholar
  3. Ao X, Fang F, Xu F (2011) Vasoactive intestinal peptide protects alveolar epithelial cells against hyperoxia via promoting the activation of STAT3. Regul Pept 168:1–4PubMedCrossRefGoogle Scholar
  4. Aujla SJ, Chan YR, Zheng M, Fei M, Askew DJ, Pociask DA, Reinhart TA, McAllister F, Edeal J, Gaus K, Husain S, Kreindler JL, Dubin PJ, Pilewski JM, Myerburg MM, Mason CA, Iwakura Y, Kolls JK (2008) IL-22 mediates mucosal host defense against Gram-negative bacterial ­pneumonia. Nat Med 14:275–281PubMedCrossRefGoogle Scholar
  5. Baltimore D (2011) NF-kappaB is 25. Nat Immunol 12:683–685PubMedCrossRefGoogle Scholar
  6. Beg AA, Sha WC, Bronson RT, Ghosh S, Baltimore D (1995) Embryonic lethality and liver ­degeneration in mice lacking the RelA component of NF-kappa B. Nature 376:167–170PubMedCrossRefGoogle Scholar
  7. Boucher RC (2007) Airway surface dehydration in cystic fibrosis: pathogenesis and therapy. Annu Rev Med 58:157–170PubMedCrossRefGoogle Scholar
  8. Bozinovski S, Jones JE, Vlahos R, Hamilton JA, Anderson GP (2002) Granulocyte/macrophage-colony-stimulating factor (GM-CSF) regulates lung innate immunity to lipopolysaccharide through Akt/Erk activation of NFkappa B and AP-1 in vivo. J Biol Chem 277:42808–42814PubMedCrossRefGoogle Scholar
  9. Bozinovski S, Jones J, Beavitt SJ, Cook AD, Hamilton JA, Anderson GP (2004) Innate immune responses to LPS in mouse lung are suppressed and reversed by neutralization of GM-CSF via repression of TLR-4. Am J Physiol Lung Cell Mol Physiol 286:L877–L885PubMedCrossRefGoogle Scholar
  10. Bromberg JF, Wrzeszczynska MH, Devgan G, Zhao Y, Pestell RG, Albanese C, Darnell JE Jr (1999) Stat3 as an oncogene. Cell 98:295–303PubMedCrossRefGoogle Scholar
  11. Bulek K, Liu C, Swaidani S, Wang L, Page RC, Gulen MF, Herjan T, Abbadi A, Qian W, Sun D, Lauer M, Hascall V, Misra S, Chance MR, Aronica M, Hamilton T, Li X (2011) The inducible kinase IKKi is required for IL-17-dependent signaling associated with neutrophilia and ­pulmonary inflammation. Nat Immunol 12:844–852PubMedCrossRefGoogle Scholar
  12. Bush A, Chodhari R, Collins N, Copeland F, Hall P, Harcourt J, Hariri M, Hogg C, Lucas J, Mitchison HM, O’Callaghan C, Phillips G (2007) Primary ciliary dyskinesia: current state of the art. Arch Dis Child 92:1136–1140PubMedCrossRefGoogle Scholar
  13. Cao Y, Vo T, Millien G, Tagne JB, Kotton D, Mason RJ, Williams MC, Ramirez MI (2010) Epigenetic mechanisms modulate thyroid transcription factor 1-mediated transcription of the surfactant protein B gene. J Biol Chem 285:2152–2164PubMedCrossRefGoogle Scholar
  14. Chen Y, Deng J, Fujimoto J, Kadara H, Men T, Lotan D, Lotan R (2010) Gprc5a deletion enhances the transformed phenotype in normal and malignant lung epithelial cells by eliciting persistent Stat3 signaling induced by autocrine leukemia inhibitory factor. Cancer Res 70:8917–8926PubMedCrossRefGoogle Scholar
  15. Cheng DS, Han W, Chen SM, Sherrill TP, Chont M, Park GY, Sheller JR, Polosukhin VV, Christman JW, Yull FE, Blackwell TS (2007) Airway epithelium controls lung inflammation and injury through the NF-kappa B pathway. J Immunol 178:6504–6513PubMedGoogle Scholar
  16. Clement CG, Evans SE, Evans CM, Hawke D, Kobayashi R, Reynolds PR, Moghaddam SJ, Scott BL, Melicoff E, Adachi R, Dickey BF, Tuvim MJ (2008) Stimulation of lung innate immunity protects against lethal pneumococcal pneumonia in mice. Am J Respir Crit Care Med 177:1322–1330PubMedCrossRefGoogle Scholar
  17. Crosby LM, Luellen C, Zhang Z, Tague LL, Sinclair SE, Waters CM (2011) Balance of life and death in alveolar epithelial type II cells: proliferation, apoptosis, and the effects of cyclic stretch on wound healing. Am J Physiol Lung Cell Mol Physiol 301:L536–L546PubMedCrossRefGoogle Scholar
  18. Dauer DJ, Ferraro B, Song L, Yu B, Mora L, Buettner R, Enkemann S, Jove R, Haura EB (2005) Stat3 regulates genes common to both wound healing and cancer. Oncogene 24:3397–3408PubMedCrossRefGoogle Scholar
  19. Dehoux MS, Boutten A, Ostinelli J, Seta N, Dombret MC, Crestani B, Deschenes M, Trouillet JL, Aubier M (1994) Compartmentalized cytokine production within the human lung in unilateral pneumonia. Am J Respir Crit Care Med 150:710–716PubMedGoogle Scholar
  20. Dubin PJ, Kolls JK (2007) IL-23 mediates inflammatory responses to mucoid Pseudomonas ­aeruginosa lung infection in mice. Am J Physiol Lung Cell Mol Physiol 292:L519–L528PubMedCrossRefGoogle Scholar
  21. Dubin PJ, Martz A, Eisenstatt JR, Fox MD, Logar A, Kolls JK (2012) IL-23 mediated inflammation in Pseudomonas aeruginosa pulmonary infection. Infect Immun 80(1):398–409PubMedCrossRefGoogle Scholar
  22. Duggan JM, You D, Cleaver JO, Larson DT, Garza RJ, Guzman Pruneda FA, Tuvim MJ, Zhang J, Dickey BF, Evans SE (2011) Synergistic interactions of TLR2/6 and TLR9 induce a high level of resistance to lung infection in mice. J Immunol 186:5916–5926PubMedCrossRefGoogle Scholar
  23. Elizur A, Adair-Kirk TL, Kelley DG, Griffin GL, Demello DE, Senior RM (2008) Tumor necrosis factor-alpha from macrophages enhances LPS-induced clara cell expression of keratinocyte-derived chemokine. Am J Respir Cell Mol Biol 38:8–15PubMedCrossRefGoogle Scholar
  24. Evans SE, Xu Y, Tuvim MJ, Dickey BF (2010a) Inducible innate resistance of lung epithelium to infection. Annu Rev Physiol 72:413–435PubMedCrossRefGoogle Scholar
  25. Evans SE, Scott BL, Clement CG, Larson DT, Kontoyiannis D, Lewis RE, Lasala PR, Pawlik J, Peterson JW, Chopra AK, Klimpel G, Bowden G, Hook M, Xu Y, Tuvim MJ, Dickey BF (2010b) Stimulated innate resistance of lung epithelium protects mice broadly against bacteria and fungi. Am J Respir Cell Mol Biol 42:40–50PubMedCrossRefGoogle Scholar
  26. Fong CH, Bebien M, Didierlaurent A, Nebauer R, Hussell T, Broide D, Karin M, Lawrence T (2008) An antiinflammatory role for IKKbeta through the inhibition of “classical” macrophage activation. J Exp Med 205:1269–1276PubMedCrossRefGoogle Scholar
  27. Franks TJ, Colby TV, Travis WD, Tuder RM, Reynolds HY, Brody AR, Cardoso WV, Crystal RG, Drake CJ, Engelhardt J, Frid M, Herzog E, Mason R, Phan SH, Randell SH, Rose MC, Stevens T, Serge J, Sunday ME, Voynow JA, Weinstein BM, Whitsett J, Williams MC (2008) Resident cellular components of the human lung: current knowledge and goals for research on cell ­phenotyping and function. Proc Am Thorac Soc 5:763–766PubMedCrossRefGoogle Scholar
  28. Freeman AF, Holland SM (2009) Clinical manifestations, etiology, and pathogenesis of the ­hyper-IgE syndromes. Pediatr Res 65:32R–37RPubMedCrossRefGoogle Scholar
  29. Freeman AF, Kleiner DE, Nadiminti H, Davis J, Quezado M, Anderson V, Puck JM, Holland SM (2007) Causes of death in hyper-IgE syndrome. J Allergy Clin Immunol 119:1234–1240PubMedCrossRefGoogle Scholar
  30. Fujisawa T, Velichko S, Thai P, Hung LY, Huang F, Wu R (2009) Regulation of airway MUC5AC expression by IL-1beta and IL-17A; the NF-kappaB paradigm. J Immunol 183:6236–6243PubMedCrossRefGoogle Scholar
  31. Fujisawa T, Chang MM, Velichko S, Thai P, Hung LY, Huang F, Phuong N, Chen Y, Wu R (2011) NF-kappaB mediates IL-1beta- and IL-17A-induced MUC5B expression in airway epithelial cells. Am J Respir Cell Mol Biol 45:246–252PubMedCrossRefGoogle Scholar
  32. Gao SP, Bromberg JF (2006) Touched and moved by STAT3. Sci STKE 2006(343):pe30PubMedCrossRefGoogle Scholar
  33. Gao H, Guo RF, Speyer CL, Reuben J, Neff TA, Hoesel LM, Riedemann NC, McClintock SD, Sarma JV, Van Rooijen N, Zetoune FS, Ward PA (2004) Stat3 activation in acute lung injury. J Immunol 172:7703–7712PubMedGoogle Scholar
  34. Gattas MV, Forteza R, Fragoso MA, Fregien N, Salas P, Salathe M, Conner GE (2009) Oxidative epithelial host defense is regulated by infectious and inflammatory stimuli. Free Radic Biol Med 47:1450–1458PubMedCrossRefGoogle Scholar
  35. Gennery AR, Flood TJ, Abinun M, Cant AJ (2000) Bone marrow transplantation does not correct the hyper IgE syndrome. Bone Marrow Transplant 25:1303–1305PubMedCrossRefGoogle Scholar
  36. Genovese MC, Cohen S, Moreland L, Lium D, Robbins S, Newmark R, Bekker P (2004) Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 50:1412–1419PubMedCrossRefGoogle Scholar
  37. Glynn P, Coakley R, Kilgallen I, Murphy N, O’Neill S (1999) Circulating interleukin 6 and interleukin 10 in community acquired pneumonia. Thorax 54:51–55PubMedCrossRefGoogle Scholar
  38. Gong MN, Thompson BT, Williams PL, Zhou W, Wang MZ, Pothier L, Christiani DC (2006) Interleukin-10 polymorphism in position −1082 and acute respiratory distress syndrome. Eur Respir J 27:674–681PubMedCrossRefGoogle Scholar
  39. Gough DJ, Corlett A, Schlessinger K, Wegrzyn J, Larner AC, Levy DE (2009) Mitochondrial STAT3 supports Ras-dependent oncogenic transformation. Science 324:1713–1716PubMedCrossRefGoogle Scholar
  40. Greenberger MJ, Strieter RM, Kunkel SL, Danforth JM, Goodman RE, Standiford TJ (1995) Neutralization of IL-10 increases survival in a murine model of Klebsiella pneumonia. J Immunol 155:722–729PubMedGoogle Scholar
  41. Gregory AD, Hogue LA, Ferkol TW, Link DC (2007) Regulation of systemic and local neutrophil responses by G-CSF during pulmonary Pseudomonas aeruginosa infection. Blood 109:3235–3243PubMedCrossRefGoogle Scholar
  42. Hajjar AM, Harowicz H, Liggitt HD, Fink PJ, Wilson CB, Skerrett SJ (2005) An essential role for non-bone marrow-derived cells in control of Pseudomonas aeruginosa pneumonia. Am J Respir Cell Mol Biol 33:470–475PubMedCrossRefGoogle Scholar
  43. Hammerschmidt S, Wolff S, Hocke A, Rosseau S, Muller E, Rohde M (2005) Illustration of ­pneumococcal polysaccharide capsule during adherence and invasion of epithelial cells. Infect Immun 73:4653–4667PubMedCrossRefGoogle Scholar
  44. Happel KI, Dubin PJ, Zheng M, Ghilardi N, Lockhart C, Quinton LJ, Odden AR, Shellito JE, Bagby GJ, Nelson S, Kolls JK (2005) Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae. J Exp Med 202:761–769PubMedCrossRefGoogle Scholar
  45. Harris TJ, Grosso JF, Yen HR, Xin H, Kortylewski M, Albesiano E, Hipkiss EL, Getnet D, Goldberg MV, Maris CH, Housseau F, Yu H, Pardoll DM, Drake CG (2007) Cutting edge: An in vivo requirement for STAT3 signaling in TH17 development and TH17-dependent ­autoimmunity. J Immunol 179:4313–4317PubMedGoogle Scholar
  46. Hayden MS, Ghosh S (2008) Shared principles in NF-kappaB signaling. Cell 132:344–362PubMedCrossRefGoogle Scholar
  47. Heymann D, L’Her E, NGuyen JM, Raher S, Canfrère I, Coupey L, Fixe P, Chailleux E, De Groote D, Praloran V, Godard A (1996) Leukaemia inhibitory factor (LIF) production in pleural ­effusions: comparison with production of IL-4, IL-8, IL-10 and macrophage-colony ­stimulating factor (M-CSF). Cytokine 8:410–416PubMedCrossRefGoogle Scholar
  48. Hoegl S, Bachmann M, Scheiermann P, Goren I, Hofstetter C, Pfeilschifter J, Zwissler B, Muhl H (2011) Protective properties of inhaled IL-22 in a model of ventilator-induced lung injury. Am J Respir Cell Mol Biol 44:369–376PubMedCrossRefGoogle Scholar
  49. Hokuto I, Ikegami M, Yoshida M, Takeda K, Akira S, Perl AK, Hull WM, Wert SE, Whitsett JA (2004) Stat-3 is required for pulmonary homeostasis during hyperoxia. J Clin Invest 113:28–37PubMedGoogle Scholar
  50. Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N, Freeman AF, Demidowich A, Davis J, Turner ML, Anderson VL, Darnell DN, Welch PA, Kuhns DB, Frucht DM, Malech HL, Gallin JI, Kobayashi SD, Whitney AR, Voyich JM, Musser JM, Woellner C, Schaffer AA, Puck JM, Grimbacher B (2007) STAT3 mutations in the hyper-IgE syndrome. N Engl J Med 357:1608–1619PubMedCrossRefGoogle Scholar
  51. Holscher C, Holscher A, Ruckerl D, Yoshimoto T, Yoshida H, Mak T, Saris C, Ehlers S (2005) The IL-27 receptor chain WSX-1 differentially regulates antibacterial immunity and survival ­during experimental tuberculosis. J Immunol 174:3534–3544PubMedGoogle Scholar
  52. Ikegami M, Falcone A, Whitsett JA (2008) STAT-3 regulates surfactant phospholipid homeostasis in normal lung and during endotoxin-mediated lung injury. J Appl Physiol 104:1753–1760PubMedCrossRefGoogle Scholar
  53. Jeyaseelan S, Chu HW, Young SK, Worthen GS (2004) Transcriptional profiling of ­lipopolysaccharide-induced acute lung injury. Infect Immun 72:7247–7256PubMedCrossRefGoogle Scholar
  54. Jeyaseelan S, Manzer R, Young SK, Yamamoto M, Akira S, Mason RJ, Worthen GS (2005) Induction of CXCL5 during inflammation in the rodent lung involves activation of alveolar epithelium. Am J Respir Cell Mol Biol 32:531–539PubMedCrossRefGoogle Scholar
  55. Jin X, Hu Z, Kang Y, Liu C, Zhou Y, Wu X, Liu J, Zhong M, Luo C, Deng L, Deng Y, Xie X, Zhang Z, Liao X (2012) Association of IL-10-1082 G/G genotype with lower mortality of acute ­respiratory distress syndrome in a Chinese population. Mol Biol Rep 39:1–4PubMedCrossRefGoogle Scholar
  56. Jones MR, Simms BT, Lupa MM, Kogan MS, Mizgerd JP (2005) Lung NF-{kappa}B activation and neutrophil recruitment require IL-1 and TNF receptor signaling during pneumococcal pneumonia. J Immunol 175:7530–7535PubMedGoogle Scholar
  57. Jones MR, Quinton LJ, Simms BT, Lupa MM, Kogan MS, Mizgerd JP (2006) Roles of ­interleukin-6 in activation of STAT proteins and recruitment of neutrophils during Escherichia coli p­neumonia. J Infect Dis 193:360–369PubMedCrossRefGoogle Scholar
  58. Jorens PG, De Jongh R, Bossaert LL, De Backer W, Herman AG, Pollet H, Bosmans E, Taupin JL, Moreau JF (1996) High levels of leukaemia inhibitory factor in ARDS. Cytokine 8:873–876PubMedCrossRefGoogle Scholar
  59. Kao CY, Chen Y, Thai P, Wachi S, Huang F, Kim C, Harper RW, Wu R (2004) IL-17 markedly up-regulates beta-defensin-2 expression in human airway epithelium via JAK and NF-kappaB signaling pathways. J Immunol 173:3482–3491PubMedGoogle Scholar
  60. Kao CY, Huang F, Chen Y, Thai P, Wachi S, Kim C, Tam L, Wu R (2005) Up-regulation of CC chemokine ligand 20 expression in human airway epithelium by IL-17 through a JAK-independent but MEK/NF-kappaB-dependent signaling pathway. J Immunol 175:6676–6685PubMedGoogle Scholar
  61. Kao CY, Kim C, Huang F, Wu R (2008) Requirements for two proximal NF-kappaB binding sites and IkappaB-zeta in IL-17A-induced human beta-defensin 2 expression by conducting airway epithelium. J Biol Chem 283:15309–15318PubMedCrossRefGoogle Scholar
  62. Kellum JA, Kong L, Fink MP, Weissfeld LA, Yealy DM, Pinsky MR, Fine J, Krichevsky A, Delude RL, Angus DC (2007) Understanding the inflammatory cytokine response in pneumonia and sepsis: results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med 167:1655–1663PubMedCrossRefGoogle Scholar
  63. Kida H, Mucenski ML, Thitoff AR, Le Cras TD, Park KS, Ikegami M, Muller W, Whitsett JA (2008) GP130-STAT3 regulates epithelial cell migration and is required for repair of the bronchiolar epithelium. Am J Pathol 172:1542–1554PubMedCrossRefGoogle Scholar
  64. Kim HS, Go H, Akira S, Chung DH (2011) TLR2-mediated production of IL-27 and chemokines by respiratory epithelial cells promotes bleomycin-induced pulmonary fibrosis in mice. J Immunol 187:4007–4017PubMedCrossRefGoogle Scholar
  65. Knapp S, Hareng L, Rijneveld AW, Bresser P, van der Zee JS, Florquin S, Hartung T, van der Poll T (2004) Activation of neutrophils and inhibition of the proinflammatory cytokine response by endogenous granulocyte colony-stimulating factor in murine pneumococcal pneumonia. J Infect Dis 189:1506–1515PubMedCrossRefGoogle Scholar
  66. Kolls JK, McCray PB Jr, Chan YR (2008) Cytokine-mediated regulation of antimicrobial proteins. Nat Rev Immunol 8:829–835PubMedCrossRefGoogle Scholar
  67. Kolsuz M, Erginel S, Alatas O, Alatas F, Metintas M, Ucgun I, Harmanci E, Colak O (2003) Acute phase reactants and cytokine levels in unilateral community-acquired pneumonia. Respiration 70:615–622PubMedCrossRefGoogle Scholar
  68. Ku CL, von Bernuth H, Picard C, Zhang SY, Chang HH, Yang K, Chrabieh M, Issekutz AC, Cunningham CK, Gallin J, Holland SM, Roifman C, Ehl S, Smart J, Tang M, Barrat FJ, Levy O, McDonald D, Day-Good NK, Miller R, Takada H, Hara T, Al-Hajjar S, Al-Ghonaium A, Speert D, Sanlaville D, Li X, Geissmann F, Vivier E, Marodi L, Garty BZ, Chapel H, Rodriguez-Gallego C, Bossuyt X, Abel L, Puel A, Casanova JL (2007) Selective predisposition to bacterial infections in IRAK-4-deficient children: IRAK-4-dependent TLRs are otherwise redundant in protective immunity. J Exp Med 204:2407–2422PubMedCrossRefGoogle Scholar
  69. Laan M, Prause O, Miyamoto M, Sjostrand M, Hytonen AM, Kaneko T, Lotvall J, Linden A (2003) A role of GM-CSF in the accumulation of neutrophils in the airways caused by IL-17 and TNF-alpha. Eur Respir J 21:387–393PubMedCrossRefGoogle Scholar
  70. Lang JE, Williams ES, Mizgerd JP, Shore SA (2008) Effect of obesity on pulmonary inflammation induced by acute ozone exposure: role of interleukin-6. Am J Physiol Lung Cell Mol Physiol 294:L1013–L1020PubMedCrossRefGoogle Scholar
  71. Li Y, Du H, Qin Y, Roberts J, Cummings OW, Yan C (2007) Activation of the signal transducers and activators of the transcription 3 pathway in alveolar epithelial cells induces inflammation and adenocarcinomas in mouse lung. Cancer Res 67:8494–8503PubMedCrossRefGoogle Scholar
  72. Lian X, Qin Y, Hossain SA, Yang L, White A, Xu H, Shipley JM, Li T, Senior RM, Du H, Yan C (2005) Overexpression of Stat3C in pulmonary epithelium protects against hyperoxic lung injury. J Immunol 174:7250–7256PubMedGoogle Scholar
  73. Liu Y, Mei J, Gonzales L, Yang G, Dai N, Wang P, Zhang P, Favara M, Malcolm KC, Guttentag S, Worthen GS (2011) IL-17A and TNF-alpha exert synergistic effects on expression of CXCL5 by alveolar type II cells in vivo and in vitro. J Immunol 186:3197–3205PubMedCrossRefGoogle Scholar
  74. Ma CS, Chew GY, Simpson N, Priyadarshi A, Wong M, Grimbacher B, Fulcher DA, Tangye SG, Cook MC (2008) Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3. J Exp Med 205:1551–1557PubMedCrossRefGoogle Scholar
  75. Mancuso P, Gottschalk A, Phare SM, Peters-Golden M, Lukacs NW, Huffnagle GB (2002) Leptin-deficient mice exhibit impaired host defense in Gram-negative pneumonia. J Immunol 168:4018–4024PubMedGoogle Scholar
  76. Mancuso P, Peters-Golden M, Goel D, Goldberg J, Brock TG, Greenwald-Yarnell M, Myers MG Jr (2011) Disruption of leptin receptor-STAT3 signaling enhances leukotriene production and pulmonary host defense against pneumococcal pneumonia. J Immunol 186:1081–1090PubMedCrossRefGoogle Scholar
  77. Marriott HM, Gascoyne KA, Gowda R, Geary I, Nicklin MJ, Iannelli F, Pozzi G, Mitchell TJ, Whyte MK, Sabroe I, Dockrell DH (2012) IL-1beta regulates CXCL8 release and influences disease outcome in response to Streptococcus pneumoniae, defining intracellular cooperation between pulmonary epithelial cells and macrophages. Infect Immun 80(3):1140–1149PubMedCrossRefGoogle Scholar
  78. Martin TR, Nakamura M, Matute-Bello G (2003) The role of apoptosis in acute lung injury. Crit Care Med 31:S184–S188PubMedCrossRefGoogle Scholar
  79. Mathur AN, Chang HC, Zisoulis DG, Stritesky GL, Yu Q, O’Malley JT, Kapur R, Levy DE, Kansas GS, Kaplan MH (2007) Stat3 and Stat4 direct development of IL-17-secreting Th cells. J Immunol 178:4901–4907PubMedGoogle Scholar
  80. Matsukawa A, Kudo S, Maeda T, Numata K, Watanabe H, Takeda K, Akira S, Ito T (2005) Stat3 in resident macrophages as a repressor protein of inflammatory response. J Immunol 175:3354–3359PubMedGoogle Scholar
  81. Matsuzaki Y, Xu Y, Ikegami M, Besnard V, Park KS, Hull WM, Wert SE, Whitsett JA (2006) Stat3 is required for cytoprotection of the respiratory epithelium during adenoviral infection. J Immunol 177:527–537PubMedGoogle Scholar
  82. McAleer JP, Kolls JK (2011) Mechanisms controlling Th17 cytokine expression and host defense. J Leukoc Biol 90:263–270PubMedCrossRefGoogle Scholar
  83. Mei J, Liu Y, Dai N, Favara M, Greene T, Jeyaseelan S, Poncz M, Lee JS, Worthen GS (2010) CXCL5 regulates chemokine scavenging and pulmonary host defense to bacterial infection. Immunity 33:106–117PubMedCrossRefGoogle Scholar
  84. Mijares LA, Wangdi T, Sokol C, Homer R, Medzhitov R, Kazmierczak BI (2011) Airway ­epithelial MyD88 restores control of Pseudomonas aeruginosa murine infection via an IL-1-dependent pathway. J Immunol 186:7080–7088PubMedCrossRefGoogle Scholar
  85. Milner JD, Brenchley JM, Laurence A, Freeman AF, Hill BJ, Elias KM, Kanno Y, Spalding C, Elloumi HZ, Paulson ML, Davis J, Hsu A, Asher AI, O’Shea J, Holland SM, Paul WE, Douek DC (2008) Impaired T(H)17 cell differentiation in subjects with autosomal dominant ­hyper-IgE syndrome. Nature 452:773–776PubMedCrossRefGoogle Scholar
  86. Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, Kawamura N, Ariga T, Pasic S, Stojkovic O, Metin A, Karasuyama H (2007) Dominant-negative mutations in the ­DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 448:1058–1062PubMedCrossRefGoogle Scholar
  87. Minegishi Y, Saito M, Nagasawa M, Takada H, Hara T, Tsuchiya S, Agematsu K, Yamada M, Kawamura N, Ariga T, Tsuge I, Karasuyama H (2009) Molecular explanation for the ­contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome. J Exp Med 206:1291–1301PubMedCrossRefGoogle Scholar
  88. Mizgerd JP (2002) Molecular mechanisms of neutrophil recruitment elicited by bacteria in the lungs. Semin Immunol 14:123–132PubMedCrossRefGoogle Scholar
  89. Mizgerd JP (2008) Acute lower respiratory tract infection. N Engl J Med 358:716–727PubMedCrossRefGoogle Scholar
  90. Mizgerd JP, Scott ML, Spieker MR, Doerschuk CM (2002) Functions of IκB proteins in inflammatory responses to E. coli LPS in mouse lungs. Am J Respir Cell Mol Biol 27:575–582PubMedGoogle Scholar
  91. Mizgerd JP, Lupa MM, Kogan MS, Warren HB, Kobzik L, Topulos GP (2003) Nuclear factor-κB p50 limits inflammation and prevents lung injury during Escherichia coli pneumonia. Am J Respir Crit Care Med 168:810–817PubMedCrossRefGoogle Scholar
  92. Mizgerd JP, Lupa MM, Hjoberg J, Vallone JC, Warren HB, Butler JP, Silverman ES (2004) Roles for early response cytokines during Escherichia coli pneumonia revealed by mice with ­combined deficiencies of all signaling receptors for TNF and IL-1. Am J Physiol Lung Cell Mol Physiol 286:L1302–L1310PubMedCrossRefGoogle Scholar
  93. Moskwa P, Lorentzen D, Excoffon KJ, Zabner J, McCray PB Jr, Nauseef WM, Dupuy C, Banfi B (2007) A novel host defense system of airways is defective in cystic fibrosis. Am J Respir Crit Care Med 175:174–183PubMedCrossRefGoogle Scholar
  94. O’Brien AD, Standiford TJ, Bucknell KA, Wilcoxen SE, Paine R (1999) Role of alveolar epithelial cell intercellular adhesion molecule-1 in host defense against Klebsiella pneumoniae. Am J Physiol 20:L961–L970Google Scholar
  95. Paine R 3rd, Morris SB, Jin H, Baleeiro CE, Wilcoxen SE (2002) ICAM-1 facilitates alveolar macrophage phagocytic activity through effects on migration over the AEC surface. Am J Physiol Lung Cell Mol Physiol 283:L180–L187PubMedGoogle Scholar
  96. Park K, Elias PM, Oda Y, Mackenzie D, Mauro T, Holleran WM, Uchida Y (2011) Regulation of cathelicidin antimicrobial peptide expression by an endoplasmic reticulum (ER) stress s­ignaling, vitamin D receptor-independent pathway. J Biol Chem 286:34121–34130PubMedCrossRefGoogle Scholar
  97. Pearl JE, Khader SA, Solache A, Gilmartin L, Ghilardi N, deSauvage F, Cooper AM (2004) IL-27 signaling compromises control of bacterial growth in mycobacteria-infected mice. J Immunol 173:7490–7496PubMedGoogle Scholar
  98. Perl AK, Wert SE, Nagy A, Lobe CG, Whitsett JA (2002) Early restriction of peripheral and ­proximal cell lineages during formation of the lung. Proc Natl Acad Sci U S A 99:10482–10487PubMedCrossRefGoogle Scholar
  99. Pittet LA, Quinton LJ, Yamamoto K, Robson BE, Ferrari JD, Algul H, Schmid RM, Mizgerd JP (2011) Earliest innate immune responses require macrophage RelA during pneumococcal pneumonia. Am J Respir Cell Mol Biol 45:573–581PubMedCrossRefGoogle Scholar
  100. Poynter ME, Irvin CG, Janssen-Heininger YM (2003) A prominent role for airway epithelial NF-kappa B activation in lipopolysaccharide-induced airway inflammation. J Immunol 170:6257–6265PubMedGoogle Scholar
  101. Quinton LJ, Mizgerd JP (2011) NF-kappaB and STAT3 signaling hubs for lung innate immunity. Cell Tissue Res 343:153–165PubMedCrossRefGoogle Scholar
  102. Quinton LJ, Nelson S, Boe DM, Zhang P, Zhong Q, Kolls JK, Bagby GJ (2002) The granulocyte colony-stimulating factor response after intrapulmonary and systemic bacterial challenges. J Infect Dis 185:1476–1482PubMedCrossRefGoogle Scholar
  103. Quinton LJ, Jones MR, Simms BT, Kogan MS, Robson BE, Skerrett SJ, Mizgerd JP (2007) Functions and regulation of NF-kappaB RelA during pneumococcal pneumonia. J Immunol 178:1896–1903PubMedGoogle Scholar
  104. Quinton LJ, Jones MR, Robson BE, Simms BT, Whitsett JA, Mizgerd JP (2008) Alveolar ­epithelial STAT3, IL-6 family cytokines, and host defense during Escherichia coli pneumonia. Am J Respir Cell Mol Biol 38:699–706PubMedCrossRefGoogle Scholar
  105. Quinton LJ, Jones MR, Robson BE, Mizgerd JP (2009) Mechanisms of the hepatic acute-phase response during bacterial pneumonia. Infect Immun 77:2417–2426PubMedCrossRefGoogle Scholar
  106. Saito M, Nagasawa M, Takada H, Hara T, Tsuchiya S, Agematsu K, Yamada M, Kawamura N, Ariga T, Tsuge I, Nonoyama S, Karasuyama H, Minegishi Y (2011) Defective IL-10 signaling in hyper-IgE syndrome results in impaired generation of tolerogenic dendritic cells and induced regulatory T cells. J Exp Med 208:235–249PubMedCrossRefGoogle Scholar
  107. Schaaf B, Rupp J, Muller-Steinhardt M, Kruse J, Boehmke F, Maass M, Zabel P, Dalhoff K (2005) The interleukin-6–174 promoter polymorphism is associated with extrapulmonary bacterial dissemination in Streptococcus pneumoniae infection. Cytokine 31:324–328PubMedCrossRefGoogle Scholar
  108. Schindler C, Levy DE, Decker T (2007) JAK-STAT signaling: from interferons to cytokines. J Biol Chem 282:20059–20063PubMedCrossRefGoogle Scholar
  109. Sen R, Baltimore D (1986) Multiple nuclear factors interact with the immunoglobulin enhancer sequences. Cell 46:705–716PubMedCrossRefGoogle Scholar
  110. Severgnini M, Takahashi S, Rozo LM, Homer RJ, Kuhn C, Jhung JW, Perides G, Steer M, Hassoun PM, Fanburg BL, Cochran BH, Simon AR (2004) Activation of the STAT pathway in acute lung injury. Am J Physiol Lung Cell Mol Physiol 286:L1282–L1292PubMedCrossRefGoogle Scholar
  111. Skerrett SJ, Liggitt HD, Hajjar AM, Wilson CB (2004a) Cutting edge: myeloid differentiation f­actor 88 is essential for pulmonary host defense against Pseudomonas aeruginosa but not Staphylococcus aureus. J Immunol 172:3377–3381PubMedGoogle Scholar
  112. Skerrett SJ, Liggitt HD, Hajjar AM, Ernst RK, Miller SI, Wilson CB (2004b) Respiratory ­epithelial cells regulate lung inflammation in response to inhaled endotoxin. Am J Physiol Lung Cell Mol Physiol 287:L143–L152PubMedCrossRefGoogle Scholar
  113. Spight D, Zhao B, Haas M, Wert S, Denenberg A, Shanley TP (2005) Immunoregulatory effects of regulated, lung-targeted expression of IL-10 in vivo. Am J Physiol Lung Cell Mol Physiol 288:L251–L265PubMedCrossRefGoogle Scholar
  114. Starner TD, Barker CK, Jia HP, Kang Y, McCray PB Jr (2003) CCL20 is an inducible product of human airway epithelia with innate immune properties. Am J Respir Cell Mol Biol 29:627–633PubMedCrossRefGoogle Scholar
  115. Sun L, Guo RF, Newstead MW, Standiford TJ, Macariola DR, Shanley TP (2009) Effect of IL-10 on neutrophil recruitment and survival after Pseudomonas aeruginosa challenge. Am J Respir Cell Mol Biol 41:76–84PubMedCrossRefGoogle Scholar
  116. Takeda K, Noguchi K, Shi W, Tanaka T, Matsumoto M, Yoshida N, Kishimoto T, Akira S (1997) Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality. Proc Natl Acad Sci U S A 94:3801–3804PubMedCrossRefGoogle Scholar
  117. Takeda K, Kaisho T, Yoshida N, Takeda J, Kishimoto T, Akira S (1998) Stat3 activation is ­responsible for IL-6-dependent T cell proliferation through preventing apoptosis: generation and characterization of T cell-specific Stat3-deficient mice. J Immunol 161:4652–4660PubMedGoogle Scholar
  118. Takeda K, Clausen BE, Kaisho T, Tsujimura T, Terada N, Forster I, Akira S (1999) Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 10:39–49PubMedCrossRefGoogle Scholar
  119. Thornton DJ, Rousseau K, McGuckin MA (2008) Structure and function of the polymeric mucins in airways mucus. Annu Rev Physiol 70:459–486PubMedCrossRefGoogle Scholar
  120. Ulich TR, Yin S, Guo K, Yi ES, Remick D, del Castillo J (1991) Intratracheal injection of ­endotoxin and cytokines. II. Interleukin-6 and transforming growth factor beta inhibit acute inflammation. Am J Pathol 138:1097–1101PubMedGoogle Scholar
  121. Ulich TR, Fann MJ, Patterson PH, Williams JH, Samal B, Del Castillo J, Yin S, Guo K, Remick DG (1994) Intratracheal injection of LPS and cytokines. V. LPS induces expression of LIF and LIF inhibits acute inflammation. Am J Physiol 267:L442–L446PubMedGoogle Scholar
  122. van der Poll T, Marchant A, Keogh CV, Goldman M, Lowry SF (1996) Interleukin-10 impairs host defense in murine pneumococcal pneumonia. J Infect Dis 174:994–1000PubMedCrossRefGoogle Scholar
  123. van der Poll T, Keogh CV, Guirao X, Buurman WA, Kopf M, Lowry SF (1997) Interleukin-6 ­gene-deficient mice show impaired defense against pneumococcal pneumonia. J Infect Dis 176:439–444PubMedCrossRefGoogle Scholar
  124. von Bernuth H, Picard C, Jin Z, Pankla R, Xiao H, Ku CL, Chrabieh M, Mustapha IB, Ghandil P, Camcioglu Y, Vasconcelos J, Sirvent N, Guedes M, Vitor AB, Herrero-Mata MJ, Arostegui JI, Rodrigo C, Alsina L, Ruiz-Ortiz E, Juan M, Fortuny C, Yague J, Anton J, Pascal M, Chang HH, Janniere L, Rose Y, Garty BZ, Chapel H, Issekutz A, Marodi L, Rodriguez-Gallego C, Banchereau J, Abel L, Li X, Chaussabel D, Puel A, Casanova JL (2008) Pyogenic bacterial infections in humans with MyD88 deficiency. Science 321:691–696CrossRefGoogle Scholar
  125. Wang J, Chen Q, Corne J, Zhu Z, Lee CG, Bhandari V, Homer RJ, Elias JA (2003) Pulmonary expression of leukemia inhibitory factor induces B cell hyperplasia and confers protection in hyperoxia. J Biol Chem 278:31226–31232PubMedCrossRefGoogle Scholar
  126. Ward NS, Waxman AB, Homer RJ, Mantell LL, Einarsson O, Du Y, Elias JA (2000) ­Interleukin-6-induced protection in hyperoxic acute lung injury. Am J Respir Cell Mol Biol 22:535–542PubMedGoogle Scholar
  127. Waxman AB, Einarsson O, Seres T, Knickelbein RG, Warshaw JB, Johnston R, Homer RJ, Elias JA (1998) Targeted lung expression of interleukin-11 enhances murine tolerance of 100% oxygen and diminishes hyperoxia-induced DNA fragmentation. J Clin Invest 101:1970–1982PubMedCrossRefGoogle Scholar
  128. Wegenka UM, Buschmann J, Lutticken C, Heinrich PC, Horn F (1993) Acute-phase response ­factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by ­interleukin-6 at the posttranslational level. Mol Cell Biol 13:276–288PubMedGoogle Scholar
  129. Wegrzyn J, Potla R, Chwae YJ, Sepuri NB, Zhang Q, Koeck T, Derecka M, Szczepanek K, Szelag M, Gornicka A, Moh A, Moghaddas S, Chen Q, Bobbili S, Cichy J, Dulak J, Baker DP, Wolfman A, Stuehr D, Hassan MO, Fu XY, Avadhani N, Drake JI, Fawcett P, Lesnefsky EJ, Larner AC (2009) Function of mitochondrial Stat3 in cellular respiration. Science 323:793–797PubMedCrossRefGoogle Scholar
  130. Wikenheiser KA, Vorbroker DK, Rice WR, Clark JC, Bachurski CJ, Oie HK, Whitsett JA (1993) Production of immortalized distal respiratory epithelial cell lines from surfactant protein C/simian virus 40 large tumor antigen transgenic mice. Proc Natl Acad Sci U S A 90:11029–11033PubMedCrossRefGoogle Scholar
  131. Woellner C, Gertz EM, Schaffer AA, Lagos M, Perro M, Glocker EO, Pietrogrande MC, Cossu F, Franco JL, Matamoros N, Pietrucha B, Heropolitanska-Pliszka E, Yeganeh M, Moin M, Espanol T, Ehl S, Gennery AR, Abinun M, Breborowicz A, Niehues T, Kilic SS, Junker A, Turvey SE, Plebani A, Sanchez B, Garty BZ, Pignata C, Cancrini C, Litzman J, Sanal O, Baumann U, Bacchetta R, Hsu AP, Davis JN, Hammarstrom L, Davies EG, Eren E, Arkwright PD, Moilanen JS, Viemann D, Khan S, Marodi L, Cant AJ, Freeman AF, Puck JM, Holland SM, Grimbacher B (2010) Mutations in STAT3 and diagnostic guidelines for hyper-IgE ­syndrome. J Allergy Clin Immunol 125(424–432):e428Google Scholar
  132. Wright JR (2005) Immunoregulatory functions of surfactant proteins. Nat Rev Immunol 5:58–68PubMedCrossRefGoogle Scholar
  133. Wu H, Suzuki T, Carey B, Trapnell BC, McCormack FX (2011a) Keratinocyte growth factor ­augments pulmonary innate immunity through epithelium-driven, GM-CSF-dependent ­paracrine activation of alveolar macrophages. J Biol Chem 286:14932–14940PubMedCrossRefGoogle Scholar
  134. Wu L, Du H, Li Y, Qu P, Yan C (2011b) Signal transducer and activator of transcription 3 (Stat3C) promotes myeloid-derived suppressor cell expansion and immune suppression during lung tumorigenesis. Am J Pathol 179:2131–2141PubMedCrossRefGoogle Scholar
  135. Wurfel MM, Gordon AC, Holden TD, Radella F, Strout J, Kajikawa O, Ruzinski JT, Rona G, Black RA, Stratton S, Jarvik GP, Hajjar AM, Nickerson DA, Rieder M, Sevransky J, Maloney JP, Moss M, Martin G, Shanholtz C, Garcia JG, Gao L, Brower R, Barnes KC, Walley KR, Russell JA, Martin TR (2008) Toll-like receptor 1 polymorphisms affect innate immune responses and outcomes in sepsis. Am J Respir Crit Care Med 178:710–720PubMedCrossRefGoogle Scholar
  136. Xing Z, Gauldie J, Cox G, Baumann H, Jordana M, Lei XF, Achong MK (1998) IL-6 is an antiinflammatory cytokine required for controlling local or systemic acute inflammatory responses. J Clin Invest 101:311–320PubMedCrossRefGoogle Scholar
  137. Xu Y, Ikegami M, Wang Y, Matsuzaki Y, Whitsett JA (2007) Gene expression and biological ­processes influenced by deletion of Stat3 in pulmonary type II epithelial cells. BMC Genomics 8:455PubMedCrossRefGoogle Scholar
  138. Yang D, Chen Q, Hoover DM, Staley P, Tucker KD, Lubkowski J, Oppenheim JJ (2003) Many chemokines including CCL20/MIP-3alpha display antimicrobial activity. J Leukoc Biol 74:448–455PubMedCrossRefGoogle Scholar
  139. Ye P, Rodriguez FH, Kanaly S, Stocking KL, Schurr J, Schwarzenberger P, Oliver P, Huang W, Zhang P, Zhang J, Shellito JE, Bagby GJ, Nelson S, Charrier K, Peschon JJ, Kolls JK (2001) Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense. J Exp Med 194:519–527PubMedCrossRefGoogle Scholar
  140. Yu FS, Cornicelli MD, Kovach MA, Newstead MW, Zeng X, Kumar A, Gao N, Yoon SG, Gallo RL, Standiford TJ (2010) Flagellin stimulates protective lung mucosal immunity: role of ­cathelicidin-related antimicrobial peptide. J Immunol 185:1142–1149PubMedCrossRefGoogle Scholar
  141. Zhong Z, Wen Z, Darnell JE Jr (1994) Stat3: a STAT family member activated by tyrosine ­phosphorylation in response to epidermal growth factor and interleukin-6. Science 264:95–98PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Lee J. Quinton
    • 1
  • Joseph P. Mizgerd
    • 1
  1. 1.Pulmonary CenterBoston University School of MedicineBostonUSA

Personalised recommendations