• Development of the immune response in pneumonia caused Klebsiella pneumoniae. Part 2

Development of the immune response in pneumonia caused Klebsiella pneumoniae. Part 2

SOVREMENNAYA PEDIATRIYA.2017.6(86):68-79; doi 10.15574/SP.2017.86.68

Abaturov O. E., Nikulina A. O.
SI «Dnіpropetrovsk Medical Academy of Ministry of Healthcare of Ukraine», Dnipro

In this paper, based on literature data, analyzed key role of proinflammatory and anti"inflammatory cytokines in the development of an immune response in pneumonia caused by Klebsiella pneumoniae. Signaling pathways that induce the production of interferons type I and II, participating in the elimination of Klebsiella pneumoniae, are described.
Key words: pneumonia, Klebsiella pneumoniae, cytokines, interferon type I and II.


1. Abaturov AE, Volosovets AP, Yulish EI. (2012). The induction of the molecular mechanisms of nonspecific protection of the respiratory tract. K., Private Drukarnya FD-II, Storozhuk OV: 240.

2. Akil H, Abbaci A, Lalloué F et al. (2015, Mar 20). IL22/IL-22R pathway induces cell survival in human glioblastoma cells. PLoS One.10(3): e0119872. https://doi.org/10.1371/journal.pone.0119872.

3. Angsana J, Chen J, Liu L, Haller CA, Chaikof EL. (2016, Jul). Efferocytosis as a regulator of macrophage chemokine receptor expression and polarization. Eur J Immunol. 46(7):1592-9. https://doi.org/10.1002/eji.201546262.

4. Arend WP. (2002, Aug-Oct). The balance between IL-1 and IL-1Ra in disease. Cytokine Growth Factor Rev. 13(4-5):323-40. https://doi.org/10.1016/S1359-6101(02)00020-5.

5. Aujla SJ, Chan YR, Zheng M. (2008, Mar). IL-22 mediates mucosal host defense against Gram-negative bacterial pneumonia. Nat Med. 14(3):275-81. https://doi.org/10.1038/nm1710.

6. Bachmann M, Scheiermann P, Härdle L, Pfeilschifter J, Mühl H. (2012, Dec 7). IL-36γ/IL-1F9, an innate T-bet target in myeloid cells. J Biol Chem. 287(50): 41684-96. https://doi.org/10.1074/jbc.M112.385443.

7. Becher B, Tugues S, Greter M. (2016, Nov 15). GM-CSF: From Growth Factor to Central Mediator of Tissue Inflammation. Immunity. 45(5):963-973. doi: 10.1016/j.immuni.2016. 10.026.

8. Behzadi P, Behzadi E, Ranjbar R. (2016, Mar). IL-12 Family Cytokines: General Characteristics, Pathogenic Microorganisms, Receptors, and Signalling Pathways. Acta Microbiol Immunol Hung. 63(1):1-25. https://doi.org/10.1556/030.63.2016.1.1.

9. Bloodworth MH, Newcomb DC, Dulek DE. (2016, Apr 22). STAT6 Signaling Attenuates Interleukin-17-Producing γδ T Cells during Acute Klebsiella pneumoniae Infection. Infect Immun. 84(5): 1548-55. https://doi.org/10.1128/IAI.00646-15.

10. Borthwick LA. (2016, Jul). The IL-1 cytokine family and its role in inflammation and fibrosis in the lung. Semin Immunopathol. 38(4):517-34. https://doi.org/10.1007/s00281-016-0559-z.

11. Cai S, Batra S, Shen L, Wakamatsu N, Jeyaseelan S. (2009, Nov 15). Both TRIF- and MyD88-dependent signaling contribute to host defense against pulmonary Klebsiella infection. J Immunol. 183(10):6629-38. https://doi.org/10.4049/jimmunol.0901033.

12. Cai S, Batra S, Wakamatsu N. (2012, Jun 1). NLRC4 inflammasome-mediated production of IL-1β modulates mucosal immunity in the lung against gram-negative bacterial infection. J Immunol. 188(11): 5623-35. doi: 0.4049/jimmunol. 1200195.

13. Campos AC, Albiero J, Ecker AB. (2016, Nov 1). Outbreak of Klebsiella pneumoniae carbapenemase-producing K pneumoniae: A systematic review. Am J Infect Control. 44(11): 1374-1380. https://doi.org/10.1016/j.ajic.2016.03.022.

14. Chakraborty K, Raundhal M, Chen BB. (2017, Jan 11). The mito-DAMP cardiolipin blocks IL-10 production causing persistent inflammation during bacterial pneumonia. Nat Commun. 8: 13944. https://doi.org/10.1038/ncomms13944.

15. Chang SH, Dong C. (2011, Jul). Signaling of interleukin-17 family cytokines in immunity and inflammation. Cell Signal. 23(7): 1069-75. https://doi.org/10.1016/j.cellsig.2010.11.022.

16. Chen K, Eddens T, Trevejo-Nunez G. (2016, Nov 9). IL-17 Receptor Signaling in the Lung Epithelium Is Required for Mucosal Chemokine Gradients and Pulmonary Host Defense against K. pneumonia. Cell Host Microbe. 20(5): 596-605.

17. Deng JC, Zeng X, Newstead M. (2004, Sep 15). STAT4 is a critical mediator of early innate immune responses against pulmonary Klebsiella infection. J Immunol. 173(6): 4075-83. https://doi.org/10.4049/jimmunol.173.6.4075.

18. Moore TA, Perry ML, Getsoian AG, Newstead MW, Standiford TJ. (2002, Nov). Divergent role of gamma interferon in a murine model of pulmonary versus systemic Klebsiella pneumoniae infection. Infect Immun. 70(11): 6310-8. https://doi.org/10.1128/IAI.70.11.6310-6318.2002.

19. Dolgachev VA, Yu B, Sun L. (2014, Apr). Interleukin 10 overexpression alters survival in the setting of gram-negative pneumonia following lung contusion. Shock. 41(4): 301-10. https://doi.org/10.1097/SHK.0000000000000123.

20. Dudakov JA, Hanash AM. (2015). van den Brink M.R. Interleukin-22: immunobiology and pathology. Annu Rev Immunol. 33: 747-85. https://doi.org/10.1146/annurev-immunol-032414-112123.

21. Duell BL, Tan CK, Carey AJ. (2012, Apr). Recent insights into microbial triggers of interleukin-10 production in the host and the impact on infectious disease pathogenesis. FEMS Immunol Med Microbiol. 64(3): 295-313. https://doi.org/10.1111/j.1574-695X.2012.00931.x.

22. Dulek DE, Newcomb DC, Goleniewska K. (2014, Sep). Allergic airway inflammation decreases lung bacterial burden following acute Klebsiella pneumoniae infection in a neutrophil- and CCL8-dependent manner. Infect Immun. 82(9): 3723-39. https://doi.org/10.1128/IAI.00035-14.

23. Eidenschenk C, Rutz S, Liesenfeld O, Ouyang W. (2014). Role of IL-22 in microbial host defense. Curr Top Microbiol Immunol. 380: 213-36. doi: 10.1007/978-3-662-43492-5-10.

24. Espinosa V, Jhingran A, Dutta O. (2014, Feb 20). Inflammatory monocytes orchestrate innate antifungal immunity in the lung. PLoS Pathog. 10(2): e1003940. https://doi.org/10.1371/journal.ppat.1003940.

25. Fagundes CT, Amaral FA, Vieira AT. (2012, Feb 1). Transient TLR activation restores inflammatory response and ability to control pulmonary bacterial infection in germfree mice. J Immunol. 188(3): 1411-20. https://doi.org/10.4049/jimmunol.1101682.

26. Floss DM, Schröder J, Franke M, Scheller J. (2015, Oct). Insights into IL-23 biology: From structure to function. Cytokine Growth Factor Rev. 26(5): 569-78. https://doi.org/10.1016/j.cytogfr.2015.07.005.

27. Fung CP, Chang FY, Lin JC. (2011, Jul). Immune response and pathophysiological features of Klebsiella pneumoniae liver abscesses in an animal model. Lab Invest. 91(7):  1029-39. https://doi.org/10.1038/labinvest.2011.52.

28. Gaffen SL. (2009, Aug). Structure and signalling in the IL-17 receptor family. Nat Rev Immunol. 9(8): 556-67. https://doi.org/10.1038/nri2586.

29. Garlanda C, Dinarello CA, Mantovani A. (2013, Dec 12). The interleukin-1 family: back to the future. Immunity. 39(6): 1003-18. https://doi.org/10.1016/j.immuni.2013.11.010.

30. Gee K, Guzzo C, Che Mat NF, Ma W, Kumar A. (2009, Mar). The IL-12 family of cytokines in infection, inflammation and autoimmune disorders. Inflamm Allergy Drug Targets. 8(1): 40-52. https://doi.org/10.2174/187152809787582507.

31. Goriely S, Neurath MF. (2008, Jan). Goldman M. How microorganisms tip the balance between interleukin-12 family members. Nat Rev Immunol. 8(1):81-6. https://doi.org/10.1038/nri2225.

32. Greenberger MJ, Kunkel SL, Strieter RM. (1996, Oct 1). IL-12 gene therapy protects mice in lethal Klebsiella pneumonia. J Immunol. 157(7): 3006-12. PMid:8816409.

33. Greenberger MJ, Strieter RM, Kunkel SL. (1995, Jul 15). Neutralization of IL-10 increases survival in a murine model of Klebsiella pneumonia. J Immunol. 155(2): 722-9. PMid:7608550.

34. Gresnigt MS, van de Veerdonk FL. (2013, Dec 15). Biology of IL-36 cytokines and their role in disease. Semin Immunol. 25(6): 458-65. https://doi.org/10.1016/j.smim.2013.11.003.

35. Guillon A, Jouan Y, Brea D. (2015, Sep). Neutrophil proteases alter the interleukin-22-receptor-dependent lung antimicrobial defence. Eur Respir J. 46(3): 771-82. https://doi.org/10.1183/09031936.00215114.

36. Hackstein H, Kranz S, Lippitsch A. (2013, Sep 17). Modulation of respiratory dendritic cells during Klebsiella pneumonia infection. Respir Res. 14: 91. https://doi.org/10.1186/1465-9921-14-91.

37. Hamilton JA. (2008, Jul). Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol. 8(7): 533-44. https://doi.org/10.1038/nri2356.

38. Happel KI, Dubin PJ, Zheng M. (2005, Sep 19). Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumonia. J Exp Med. 202(6): 761-9. https://doi.org/10.1084/jem.20050193; PMid:16157683 PMCid:PMC2212952

39. Hasegawa H, Mizoguchi I, Chiba Y. (2016, Nov 4). Expanding Diversity in Molecular Structures and Functions of the IL-6/IL-12 Heterodimeric Cytokine Family. Front Immunol. 7: 479. https://doi.org/10.3389/fimmu.2016.00479.

40. Holden VI, Breen P,  Houle S. (2016, Sep-Oct).  Klebsiella pneumoniae siderophores induce inflammation, bacterial dissemination, and HIF-1α stabilization during pneumonia. mBio. 7(5): e01397-16. Published online Sep 13. https://doi.org/10.1128/mBio.01397-16.

41. Hoogerwerf JJ, van der Windt GJ, Blok DC. (2012, Sep 25). Interleukin-1 receptor-associated kinase M-deficient mice demonstrate an improved host defense during Gram-negative pneumonia. Mol Med. 18: 1067-75. https://doi.org/10.2119/molmed.2011.00450.

42. Hsieh PF, Hsu R, Chen CT, Lin TL, Wang JT. (2016, Jul 3) The Klebsiella pneumoniae YfgL (BamB) lipoprotein contributes to outer membrane protein biogenesis, type-1 fimbriae expression, anti-phagocytosis, and in vivo virulence. Virulence. 7(5): 587-601. https://doi.org/10.1080/21505594.2016.1171435.

43. Huet O, Pickering RJ, Tikellis C. (2016, Oct 3). Protective Effect of Inflammasome Activation by Hydrogen Peroxide in a Mouse Model of Septic Shock. Crit Care Med. https://doi.org/10.1097/CCM.0000000000002070.

44. Inoue M, Arikawa T, Chen YH. (2014, Apr 8). T cells down-regulate macrophage TNF production by IRAK1-mediated IL-10 expression and control innate hyperinflammation. Proc Natl Acad Sci U S A. 111(14): 5295-300. https://doi.org/10.1073/pnas.1321427111.

45. Iriguchi S, Kikuchi N, Kaneko S. (2015, Jan 8). T-cell-restricted T-bet overexpression induces aberrant hematopoiesis of myeloid cells and impairs function of macrophages in the lung. Blood. 125(2): 370-82. https://doi.org/10.1182/blood-2014-05-575225.

46. Isler P, de Rochemonteix BG, Songeon F, Boehringer N, Nicod LP. (1999, Feb). Interleukin-12 production by human alveolar macrophages is controlled by the autocrine production of interleukin-10. Am J Respir Cell Mol Biol. 20(2): 270-8. https://doi.org/10.1165/ajrcmb.20.2.3313.

47. Khawar MB, Azam F, Sheikh N, Abdul Mujeeb K. (2016). How Does Interleukin-22 Mediate Liver Regeneration and Prevent Injury and Fibrosis? J Immunol Res. 2016: 2148129. https://doi.org/10.1155/2016/2148129.

48. Kimani SG, Geng K, Kasikara C. (2014, Nov 10). Contribution of Defective PS Recognition and Efferocytosis to Chronic Inflammation and Autoimmunity. Front Immunol. 5: 566. https://doi.org/10.3389/fimmu.2014.00566.

49. Kishimoto T. (2006). Interleukin-6: discovery of a pleiotropic cytokine. Arthritis Res Ther. 8; Suppl 2: S2. https://doi.org/10.1186/ar1916.

50. Kovach MA, Singer BH, Newstead MW et al. (2016, Aug). IL-36γ is secreted in microparticles and exosomes by lung macrophages in response to bacteria and bacterial components. J Leukoc Biol. 100(2): 413-21. https://doi.org/10.1189/jlb.4A0315-087R.

51. Kovtonyuk LV, Fritsch K, Feng X, Manz MG, Takizawa H. (2016, Nov 14). Inflamm-Aging of Hematopoiesis, Hematopoietic Stem Cells, and the Bone Marrow Microenvironment. Front Immunol. 7: 502. https://doi.org/10.3389/fimmu.2016.00502.

52. Kumar P, Subramaniyam G. (2015, Feb). Molecular underpinnings of Th17 immune-regulation and their implications in autoimmune diabetes. Cytokine. 71(2): 366-76. https://doi.org/10.1016/j.cyto.2014.10.010.

53. Laichalk LL, Bucknell KA, Huffnagle GB et al. (1998, Jun). Intrapulmonary delivery of tumor necrosis factor agonist peptide augments host defense in murine gram-negative bacterial pneumonia. Infect Immun. 66(6): 2822-6. PMid:9596755 PMCid:PMC108277.

54. Laichalk LL, Kunkel SL, Strieter RM et al (1996, Dec). Tumor necrosis factor mediates lung antibacterial host defense in murine Klebsiella pneumonia. Infect Immun. 64(12): 5211-8. PMid:8945568 PMCid:PMC174510.

55. Lee W, Huang JL, Yeh KW et al. (2011, Dec). Immune defects in active mycobacterial diseases in patients with primary immunodeficiency diseases (PIDs). J Formos Med Assoc. 110(12): 750-8. https://doi.org/10.1016/j.jfma.2011.11.004.

56. Li A, Gan Y, Wang R et al. (2015). IL-22 Up-Regulates β-Defensin-2 Expression in Human Alveolar Epithelium via STAT3 but Not NF-κB Signaling Pathway. Inflammation. 38(3): 1191-200. https://doi.org/10.1007/s10753-014-0083-z.

57. Lin YC, Lu MC, Lin C et al. (2013, Nov 6). Activation of IFN-γ/STAT/IRF-1 in hepatic responses to Klebsiella pneumoniae infection. PLoS One. 8(11): e79961. https://doi.org/10.1371/journal.pone.0079961.

58. Lindell DM, Standiford TJ, Mancuso P et al. (2001, Oct). Macrophage inflammatory protein 1alpha/CCL3 is required for clearance of an acute Klebsiella pneumoniae pulmonary infection. Infect Immun. 69(10): 6364-9. https://doi.org/10.1128/IAI.69.10.6364-6369.2001.

59. Mancilla J, García P, Dinarello CA. (1993, Mar). The interleukin-1 receptor antagonist can either reduce or enhance the lethality of Klebsiella pneumoniae sepsis in newborn rats. Infect Immun. 61(3): 926-32. PMid:8432613 PMCid:PMC302821.

60. Martin JC, Bériou G, Heslan M et al. (2014, Jan). Interleukin-22 binding protein (IL-22BP) is constitutively expressed by a subset of conventional dendritic cells and is strongly induced by retinoic acid. Mucosal Immunol. 7(1): 101-13. https://doi.org/10.1038/mi.2013.28.

61. Massberg S, Schaerli P, Knezevic-Maramica I et al. (2007, Nov 30). Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell. 131(5): 994-1008. https://doi.org/10.1016/j.cell.2007.09.047.

62. Mina MJ, Brown LA, Klugman KP. (2015, Jun). Dynamics of Increasing IFN-γ Exposure on Murine MH-S Cell-Line Alveolar Macrophage Phagocytosis of Streptococcus pneumonia. J Interferon Cytokine Res. 35(6): 474-9. https://doi.org/10.1089/jir.2014.0087.

63. Moore TA, Perry ML, Getsoian AG et al. (2003, Sep). Increased mortality and dysregulated cytokine production in tumor necrosis factor receptor 1-deficient mice following systemic Klebsiella pneumoniae infection. Infect Immun. 71(9): 4891-900. https://doi.org/10.1128/IAI.71.9.4891-4900.2003.

64. Morris M, Li L. (2012, Feb). Molecular mechanisms and pathological consequences of endotoxin tolerance and priming. Arch Immunol Ther Exp (Warsz). 60(1): 13-8. https://doi.org/10.1007/s00005-011-0155-9.

65. Murakami T, Hatano S, Yamada H, Iwakura Y, Yoshikai Y. (2016, Dec 1). Two Types of Interleukin 17A-Producing γδ T Cells in Protection Against Pulmonary Infection With Klebsiella pneumonia. J Infect Dis. 214(11): 1752-1761. https://doi.org/10.1093/infdis/jiw443.

66. Naka T, Nishimoto N, Kishimoto T. (2002). The paradigm of IL-6: from basic science to medicine. Arthritis Res. 4; Suppl 3: S233-42. https://doi.org/10.1186/ar565.

67. Ness-Schwickerath KJ, Morita CT. (2011, Jul). Regulation and function of IL-17A- and IL-22-producing γδ T cells. Cell Mol Life Sci. 68(14): 2371-90. https://doi.org/10.1007/s00018-011-0700-z.

68. Nishida A, Hidaka K, Kanda T et al. (2016, Feb). Increased Expression of Interleukin-36, a Member of the Interleukin-1 Cytokine Family, in Inflammatory Bowel Disease. Inflamm Bowel Dis. 22(2): 303-14. https://doi.org/10.1097/MIB.0000000000000654.

69. Oguz SS, Sipahi E, Dilmen U. (2011, May). C-reactive protein and interleukin-6 responses for differentiating fungal and bacterial aetiology in late-onset neonatal sepsis. Mycoses. 54(3): 212-6. https://doi.org/10.1111/j.1439-0507.2009.01802.x.

70. Paczosa MK, Mecsas J. (2016, Jun 15). Klebsiella pneumoniae : Going on the Offense with a Strong Defense. Microbiol Mol Biol Rev. 80(3): 629-61. https://doi.org/10.1128/MMBR.00078-15.

71. Pantelidou IM, Galani I, Georgitsi M, Daikos GL, Giamarellos-Bourboulis EJ. (2015, Nov). Interactions of Klebsiella pneumoniae with the innate immune system vary in relation to clone and resistance phenotype. Antimicrob Agents Chemother. 59(11): 7036-43. https://doi.org/10.1128/AAC.01405-15.

72. Parker D, Ahn D, Cohen T, Prince A. (2016, Jan). Innate Immune Signaling Activated by MDR Bacteria in the Airway. Physiol Rev. 96(1): 19-53. https://doi.org/10.1152/physrev.00009.2015.

73. Pedraza S, Lezana JL, Samarina A et al. (2010, Oct). Clinical disease caused by Klebsiella in 2 unrelated patients with interleukin 12 receptor beta1 deficiency. Pediatrics. 126(4): e971-6. https://doi.org/10.1542/peds.2009-2504.

74. Poe SL, Arora M, Oriss TB et al. (2013, Jan). STAT1-regulated lung MDSC-like cells produce IL-10 and efferocytose apoptotic neutrophils with relevance in resolution of bacterial pneumonia. Mucosal Immunol. 6(1): 189-99. https://doi.org/10.1038/mi.2012.62.

75. Ramirez-Alejo N, Santos-Argumedo L. (2014, May). Innate defects of the IL-12/IFN-γ axis in susceptibility to infections by mycobacteria and salmonella. J Interferon Cytokine Res. 34(5): 307-17. https://doi.org/10.1089/jir.2013.0050.

76. Rösler B, Herold S. (2016, Dec). Lung epithelial GM-CSF improves host defense function and epithelial repair in influenza virus pneumonia-a new therapeutic strategy? Mol Cell Pediatr. 3(1): 29. https://doi.org/10.1186/s40348-016-0055-5.

77. Rubini A. (2013, Oct). Interleukin-6 and lung inflammation: evidence for a causative role in inducing respiratory system resistance increments. Inflamm Allergy Drug Targets. 12(5): 315-21. https://doi.org/10.2174/1871528111312050003; PMid:23859697

78. Rukavina T, Ticac B, Vasiljev V. (2006). IL-10 in antilipopolysaccharide immunity against systemic Klebsiella infections. Mediators Inflamm. 2006(6): 69431. https://doi.org/10.1155/MI/2006/69431.

79. Rukavina T, Vasiljev V, Ticac B. (2005, Jun 9). Proinflammatory cytokines in antilipopolysaccharide immunity against Klebsiella infections. Mediators Inflamm. 2005(2): 88-95. https://doi.org/10.1155/MI.2005.88.

80. Satorres SE, Alcaráz LE, Cargnelutti E, Di Genaro MS. (2009, Apr 27). IFN-gamma plays a detrimental role in murine defense against nasal colonization of Staphylococcus aureus. Immunol Lett. 123(2): 185-8. https://doi.org/10.1016/j.imlet.2009.03.003.

81. Shiomi A, Usui T. (2015). Pivotal roles of GM-CSF in autoimmunity and inflammation. Mediators Inflamm. 2015: 568543. https://doi.org/10.1155/2015/568543.

82. Sims JE, Smith DE. (2010, Feb). The IL-1 family: regulators of immunity. Nat Rev Immunol. 10(2): 89-102. https://doi.org/10.1038/nri2691.

83. Sismanopoulos N, Delivanis DA, Alysandratos KD et al. (2012). Mast cells in allergic and inflammatory diseases. Curr Pharm Des. 18(16): 2261-77. doi 10.2174/138161212 800165997.

84. Song X, Qian Y. (2013, May). The activation and regulation of IL-17 receptor mediated signaling. Cytokine. 62(2): 175-82. https://doi.org/10.1016/j.cyto.2013.03.014.

85. Standiford LR, Standiford TJ, Newstead MJ et al. (2012, Mar 1). TLR4-dependent GM-CSF protects against lung injury in Gram-negative bacterial pneumonia. Am J Physiol Lung Cell Mol Physiol. 302(5): L447-54. https://doi.org/10.1152/ajplung.00415.2010.

86. Sun L, Cornell TT, LeVine A et al. (2013, May). Dual role of interleukin-10 in the regulation of respiratory syncitial virus (RSV)-induced lung inflammation. Clin Exp Immunol. 172(2): 263-79. https://doi.org/10.1111/cei.12059.

87. Sun L, Louie MC, Vannella KM et al. (2011, Mar). New concepts of IL-10-induced lung fibrosis: fibrocyte recruitment and M2 activation in a CCL2/CCR2 axis. Am J Physiol Lung Cell Mol Physiol. 300(3): L341-53. https://doi.org/10.1152/ajplung.00122.2010.

88. Sun L, Zhu Z, Cheng N, Yan Q, Ye RD. (2014, Jul). Serum amyloid A induces interleukin-33 expression through an IRF7-dependent pathway. Eur J Immunol. 44(7): 2153-64. https://doi.org/10.1002/eji.201344310.

89. Sutherland RE, Olsen JS, McKinstry A, Villalta SA, Wolters PJ. (2008, Oct 15). Mast cell IL-6 improves survival from Klebsiella pneumonia and sepsis by enhancing neutrophil killing. J Immunol. 181(8): 5598-605. https://doi.org/10.4049/jimmunol.181.8.5598.

90. Sutton CE, Lalor SJ, Sweeney CM et al. (2009, Aug 21). Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity. 31(2): 331-41. https://doi.org/10.1016/j.immuni.2009.08.001.

91. Tanabe M, Matsumoto T, Shibuya K et al (2005, Jan). Compensatory response of IL-1 gene knockout mice after pulmonary infection with Klebsiella pneumonia. J Med Microbiol. 54; Pt 1: 7-13. https://doi.org/10.1099/jmm.0.45736-0.

92. Theoharides TC, Alysandratos KD, Angelidou A et al. (2012, Jan). Mast cells and inflammation. Biochim Biophys Acta. 1822(1): 21-33. https://doi.org/10.1016/j.bbadis.2010.12.014.

93. Thomsen KL. (2013, Apr). Regulation of urea synthesis during the acute phase response in rats. Dan Med J. 60(4): B4617. PMID: 23651724. https://doi.org/10.1152/ajpgi.00416.2012

94. Toyonaga T, Hino O, Sugai S et al. (1994, Jan 18). Chronic active hepatitis in transgenic mice expressing interferon-gamma in the liver. Proc Natl Acad Sci USA. 91(2): 614-8. https://doi.org/10.1073/pnas.91.2.614; PMid:8290572 PMCid:PMC42999.

95. Ushach I, Zlotnik A. (2016, Sep). Biological role of granulocyte macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) on cells of the myeloid lineage. J Leukoc Biol. 100(3): 481-9. https://doi.org/10.1189/jlb.3RU0316-144R.

96. Van Enckevort FH, Sweep CG, Span PN et al. (2001, Oct-Dec). Reduced adrenal response and increased mortality after systemic Klebsiella pneumoniae infection in interleukin-6-deficient mice. Eur Cytokine Netw. 12(4): 581-6. PMid:11781184.

97. Van Lieshout MH, Florquin S, Vanʼt Veer C, de Vos AF, van der Poll T. (2015). TIR-Domain-Containing Adaptor-Inducing Interferon-β (TRIF) Mediates Antibacterial Defense during Gram-Negative Pneumonia by Inducing Interferon-x03B3. J Innate Immun. 7(6): 637-46. https://doi.org/10.1159/000430913.

98. Vignali DA, Kuchroo VK. (2012, Jul 19). IL-12 family cytokines: immunological playmakers. Nat Immunol. 13(8): 722-8. https://doi.org/10.1038/ni.2366.

99. Wang N, Liang H, Zen K et al. (2014, Nov 28). Molecular mechanisms that influence the macrophage m1-m2 polarization balance. Front Immunol. 5: 614. https://doi.org/10.3389/fimmu.2014.00614.

100. Winkle SM, Throop AL, Herbst-Kralovetz MM. (2016, Jun 17). IL-36γ Augments Host Defense and Immune Responses in Human Female Reproductive Tract Epithelial Cells. Front Microbiol. 7: 955. https://doi.org/10.3389/fmicb.2016.00955.

101. Witte E, Witte K, Warszawska K, Sabat R, Wolk K. (2010, Oct). Interleukin-22: a cytokine produced by T, NK and NKT cell subsets, with importance in the innate immune defense and tissue protection. Cytokine Growth Factor Rev. 21(5): 365-79. doi 10.1016/j. cytogfr. 2010.08.002.

102. Wolk K, Witte E, Witte K, Warszawska K, Sabat R. (2010, Mar). Biology of interleukin-22. Semin Immunopathol. 32(1): 17-31. https://doi.org/10.1007/s00281-009-0188-x.

103. Wu F, Xu J, Huang Q et al. (2016). The Role of Interleukin-17 in Lung Cancer. Mediators Inflamm. 2016: 8494079. https://doi.org/10.1155/2016/8494079; PMid:27872514 PMCid:PMC5107223

104. Xu X, Weiss ID, Zhang HH et al. (2014, Feb 15). Conventional NK cells can produce IL-22 and promote host defense in Klebsiella pneumoniae pneumonia. J Immunol. 192(4): 1778-86. https://doi.org/10.4049/jimmunol.1300039.

105. Yamada M, Gomez JC, Chugh PE et al. (2011, May 15). Interferon-γ production by neutrophils during bacterial pneumonia in mice. Am J Respir Crit Care Med. 183(10): 1391-401. https://doi.org/10.1164/rccm.201004-0592OC.

106. Yao X, Huang J, Zhong H et al. (2014, Feb). Targeting interleukin-6 in inflammatory autoimmune diseases and cancers. Pharmacol Ther. 141(2): 125-39. https://doi.org/10.1016/j.pharmthera.2013.09.004.

107. Ye P, Garvey PB, Zhang P et al. (2001, Sep). Interleukin-17 and lung host defense against Klebsiella pneumoniae infection. Am J Respir Cell Mol Biol. 25(3): 335-40. https://doi.org/10.1165/ajrcmb.25.3.4424.

108. Ye P, Rodriguez FH, Kanaly S et al. (2001, Aug 20). 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(4): 519-27. https://doi.org/10.1084/jem.194.4.519; PMid:11514607 PMCid:PMC2193502.

109. Yoshida K, Matsumoto T, Tateda K et al. (2001, May). Induction of interleukin-10 and down-regulation of cytokine production by Klebsiella pneumoniae capsule in mice with pulmonary infection. J Med Microbiol. 50(5): 456-61. https://doi.org/10.1099/0022-1317-50-5-456.