The role of proinflammatory and anti-inflammatory cytokines in bacterial pneumonia. Review
PDF_2021-1_77-89 (Русский)
HTML_2021-1_77-89 (Русский)



How to Cite

Zinina EP, Tsarenko SV, Logunov DY, Tukhvatulin AI, Babayants AV, Avramov АА The role of proinflammatory and anti-inflammatory cytokines in bacterial pneumonia. Review. Annals of Critical Care. 2021;(1):77–89. doi:10.21320/1818-474X-2021-1-77-89.


Abstract Views: 8
PDF_2021-1_77-89 (Русский) Downloads: 1
HTML_2021-1_77-89 (Русский) Downloads: 0
Plum Analytics


English Русский

Social Networks




Hospital-acquired pneumonia is a common cause of mortality in intensive care units. Therapy effectiveness depends on the antibiotic regimen chosen. Serum cytokines concentrations could be used as sensitive predictors of hospital-acquired pneumonia outcomes and therapy response. Analysis of literature in the Pubmed database shows, that using the key terms “pneumonia”, “cytokines” and “biomarkers”, 1062 publications can be found. By narrowing the search with key terms “nosocomial pneumonia” and “cytokines” it is possible to discover 212 publications. The search for literature, regarding information on specific cytokines and their role in bacterial pneumonia yields another 258 articles. Both experimental and clinical studies revealed the potential prognostic value of cytokines as diagnostic biomarkers in bacterial pneumonia. In this paper we review the pathogenesis of pneumonia-related inflammation, related cytokines, and their practical value. Information regarding interleukins, interferons, tumor necrosis factor superfamily proteins, matrix metalloproteinases, colony-stimulating factors, chemokines, and anti-inflammatory cytokines was reviewed. Many inflammatory factors have yet to be thoroughly researched. Furthermore, more studies are necessary to determine the prognostic potential of cytokines as markers of the effectiveness of antibacterial therapy in nosocomial pneumonia.
PDF_2021-1_77-89 (Русский)
HTML_2021-1_77-89 (Русский)


  1. Чучалин А.Г., Синопальников А.И., Козлов Р.С. и др. Внебольничная пневмония у взрослых. Практические рекомендации по диагностике, лечению и профилактике (пособие для врачей). Клин. микробиол. антимикроб. химиотер. 2010; 12(3): 186–225. [Community-acquired pneumonia in adults: practical recommendations for diagnosis, treatment and prevention. Clinical Microbiology and Antimicrobial Chemotherapy [Klinicheskaya Mikrobiologiya i Antimikrobnaya Khimioterapiya] 2010; 12(3): 186–225. (In Russ)]
  2. Нозокомиальная пневмония у взрослых: Российские национальные рекомендации / под ред. акад. РАН Б.Р.Гельфанда; 2-е изд. М.: Медицинское информационное агентство, 2016. [Nosocomial pneumonia of adults: Russian national guidelines / Main editor B.R. Gelfand; 2nd ed. Moscow: Medical information agency, 2016. (In Russ)]
  3. Leone M., Bouadma L., Bouhemad B., et al. Hospital-acquired pneumonia in ICU. Anaesth Crit Care Pain Med. 2018; 37(1): 83–98. DOI: 10.1016/j.accpm.2017.11.006
  4. Lanks C.W., Musani A.I., Hsia D.W. Community-acquired Pneumonia and Hospital-acquired Pneumonia. Med Clin North Am. 2019; 103(3): 487– DOI: 10.1016/j.mcna.2018.12.008
  5. Ferrer M., Torres A. Epidemiology of ICU-acquired pneumonia. Curr Opin Crit Care. 2018; 24(5): 325–331. DOI: 10.1097/MCC.0000000000000536
  6. Barbier F., Andremont A., Wolff M., et al. Hospital-acquired pneumonia and ventilator-associated pneumonia: Recent advances in epidemiology and management. Curr Opin Pulm Med. 2013; 19(3): 216–228. DOI: 10.1097/MCP.0b013e32835f27be
  7. Torres A., Niederman M.S., Chastre J., et al. International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia. Eur Respir J. 2017; 50(3). DOI: 10.1183/13993003.00582-2017
  8. Karakioulaki M., Stolz D. Biomarkers in pneumonia-beyond procalcitonin. Int J Mol Sci. 2019; 20(8). DOI: 10.3390/ijms20082004
  9. Wu B.G., Segal L.N. The Lung Microbiome and Its Role in Pneumonia. Clin Chest Med. 2018; 39(4): 677–689. DOI: 10.1016/j.ccm.2018.07.003
  10. Mizgerd J.P. Inflammation and Pneumonia: Why Are Some More Susceptible than Others? Clin Chest Med. 2018; 39(4): 669–676. DOI: 10.1016/j.ccm.2018.07.002
  11. Cazzola M., Matera M.G., Pezzuto G. Inflammation — A new therapeutic target in pneumonia. Respiration. 2005; 72(2): 117–126. DOI: 10.1159/000084039
  12. Pandolfi F., Altamura S., Frosali S., et al. Key Role of DAMP in Inflammation, Cancer, and Tissue Repair. Clin Ther. 2016; 38(5): 1017–1028. DOI: 10.1016/j.clinthera.2016.02.028
  13. Nicaise V., Roux M., Zipfel C. Recent advances in PAMP-Triggered immunity against bacteria: Pattern recognition receptors watch over and raise the alarm. Plant Physiol. 2009; 150(4): 1638–1647. DOI: 10.1104/pp.109.139709
  14. Zipfel C. Early molecular events in PAMP-triggered immunity. Curr Opin Plant Biol. 2009; 12(4): 414–420. DOI: 10.1016/j.pbi.2009.06.003
  15. Gong T., Liu L., Jiang W., et al. DAMP-sensing receptors in sterile inflammation and inflammatory diseases. Nat Rev Immunol. 2020; 20(2): 95–112. DOI: 10.1038/s41577-019-0215-7
  16. Suwara M.I., Green N.J., Borthwick L.A., et al. IL-1a released from damaged epithelial cells is sufficient and essential to trigger inflammatory responses in human lung fibroblasts. Mucosal Immunol. 2014; 7(3): 684–693. DOI: 10.1038/mi.2013.87
  17. Pichavant M., Taront S., Jeannin P., et al. Impact of Bronchial Epithelium on Dendritic Cell Migration and Function: Modulation by the Bacterial Motif KpOmpA. J Immunol. 2006; 177(9): 5912–5919. DOI: 10.4049/jimmunol.177.9.5912
  18. Marongiu L., Gornati L., Artuso I., et al. Below the surface: The inner lives of TLR4 and TLR9. J Leukoc Biol. 2019; 106(1): 147–160. DOI: 10.1002/JLB.3MIR1218-483RR
  19. Koppe U., Suttorp N., Opitz B. Recognition of Streptococcus pneumoniae by the innate immune system. Cell Microbiol. 2012; 14(4): 460–466. DOI: 10.1111/j.1462-5822.2011.01746.x
  20. Rabes A., Suttorp N., Opitz B. Inflammasomes in pneumococcal infection: Innate immune sensing and bacterial evasion strategies. In: Current Topics in Microbiology and Immunology. Springer Verlag. 2016; 397: 215–227. DOI: 10.1007/978-3-319-41171-2_11
  21. Fang R., Tsuchiya K., Kawamura I., et al. Critical Roles of ASC Inflammasomes in Caspase-1 Activation and Host Innate Resistance to Streptococcus pneumoniae Infection . J Immunol. 2011; 187(9): 4890–4899. DOI: 10.4049/jimmunol.1100381
  22. Kumar S.R., Paudel S., Ghimire L., et al. Emerging roles of inflammasomes in acute pneumonia. Am J Respir Crit Care Med. 2018; 197(2): 160–171. DOI: 10.1164/rccm.201707-1391PP
  23. Grousd J.A., Rich H.E., Alcorn J.F. Host-pathogen interactions in gram-positive bacterial pneumonia. Clin Microbiol Rev. 2019; 32(3). DOI: 10.1128/CMR.00107-18
  24. Ugolini M., Sander L.E. Dead or alive: how the immune system detects microbial viability. Curr Opin Immunol. 2019; 56: 60–66. DOI: 10.1016/j.coi.2018.09.018
  25. Herr C., Shaykhiev R., Bals R. The role of cathelicidin and defensins in pulmonary inflammatory diseases. Expert Opin Biol Ther. 2007; 7(9): 1449–1461. DOI: 10.1517/14712598.7.9.1449
  26. Potey P.M.D., Rossi A.G., Lucas C.D., et al. Neutrophils in the initiation and resolution of acute pulmonary inflammation: understanding biological function and therapeutic potential. J Pathol. 2019; 247(5): 672–685. DOI: 10.1002/path.5221
  27. Teoh C., Tan S., Tran T. Integrins as Therapeutic Targets for Respiratory Diseases. Curr Mol Med. 2015; 15(8): 714–734. DOI: 10.2174/1566524015666150921105339
  28. Chiu C., Openshaw P.J. Antiviral B cell and T cell immunity in the lungs. Nat Immunol. 2015; 16(1): 18–26. DOI: 10.1038/ni.3056
  29. Aziz M., Holodick N.E., Rothstein T.L., et al. The role of B-1 cells in inflammation. Immunol Res. 2015; 63(1–3): 153–166. DOI: 10.1007/s12026-015-8708-3
  30. Gustafson C.E., Weyand C.M., Goronzy J.J. T follicular helper cell development and functionality in immune ageing. Clin Sci. 2018; 132(17): 1925–1935. DOI: 10.1042/CS20171157
  31. Chalifour A., Jeannin P., Gauchat J.F., et al. Direct bacterial protein PAMP recognition by human NK cells involves TLRs and triggers α-defensin production. Blood. 2004; 104(6): 1778–1783. DOI: 10.1182/blood-2003-08-2820
  32. Habets M.G.J.L., Rozen D.E., Brockhurst M.A. Variation in Streptococcus pneumoniae susceptibility to human antimicrobial peptides may mediate intraspecific competition. Proc R Soc B Biol Sci. 2012; 279(1743): 3803–3811. DOI: 10.1098/rspb.2012.1118
  33. Riquelme S.A., Ahn D., Prince A. Pseudomonas aeruginosa and Klebsiella pneumoniae Adaptation to Innate Immune Clearance Mechanisms in the Lung. J Innate Immun. 2018; 10(5–6): 442–454. DOI: 10.1159/000487515
  34. Inforzato A., Bottazzi B., Garlanda C., et al. Pentraxins in humoral innate immunity. Adv Exp Med Biol. 2012; 946: 1–20. DOI: 10.1007/978-1-4614-0106-3_1
  35. Johnston L.K., Rims C.R., Gill S.E., et al. Pulmonary macrophage subpopulations in the induction and resolution of acute lung injury. Am J Respir Cell Mol Biol. 2012; 47(4): 417–426. DOI: 10.1165/rcmb.2012-0090OC
  36. Dinarello C.A. Overview of the IL-1 family in innate inflammation and acquired immunity. Immunol Rev. 2018; 281(1): 8–27. DOI: 10.1111/imr.12621
  37. Hamza T., Barnett J.B., Li B. Interleukin 12 a key immunoregulatory cytokine in infection applications. Int J Mol Sci. 2010; 11(3): 789–806. DOI: 10.3390/ijms11030789
  38. Brat D.J., Bellail A.C., Van Meir E.G. The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro Oncol. 2005; 7(2): 122–133. DOI: 10.1215/S1152851704001061
  39. Steinhauser M.L., Hogaboam C.M., Lukacs N.W., et al. Multiple roles for IL-12 in a model of acute septic peritonitis. J Immunol. 1999; 162(9): 5437–5443.
  40. Billiau A., Matthys P. Interferon-gamma: a historical perspective. Cytokine Growth Factor Rev. 2009; 20(2): 97–113. DOI: 10.1016/j.cytogfr.2009.02.004
  41. Meyer O. Interferons and autoimmune disorders. Joint Bone Spine. 2009; 76(5): 464–473. DOI: 10.1016/j.jbspin.2009.03.012
  42. Hertzog P., Forster S., Samarajiwa S. Systems biology of interferon responses. J Interferon Cytokine Res. 2011; 31(1): 5–11. DOI: 10.1089/jir.2010.0126
  43. Hu X., Ivashkiv L.B. Cross-regulation of signaling pathways by interferon-gamma: implications for immune responses and autoimmune diseases. Immunity. 2009; 31(4): 539–550. DOI: 10.1016/j.immuni.2009.09.002
  44. Baudino L., Azeredo da Silveira S., Nakata M., et al. Molecular and cellular basis for pathogenicity of autoantibodies: lessons from murine monoclonal autoantibodies. Springer Semin Immunopathol. 2006; 28(2): 175–184. DOI: 10.1007/s00281-006-0037-0
  45. Gomez J.C., Yamada M., Martin J.R., et al. Mechanisms of interferon-gamma production by neutrophils and its function during Streptococcus pneumoniae pneumonia. Am J Respir Cell Mol Biol. 2015; 52(3): 349–364. DOI: 10.1165/rcmb.2013-0316OC
  46. Jeong D.-G., Seo J.-H., Heo S.-H., et al. Tumor necrosis factor-alpha deficiency impairs host defense against Streptococcus pneumoniae . Lab Anim Res. 2015; 31(2): 78. DOI: 10.5625/lar.2015.31.2.78
  47. Suga M., Iyonaga K., Okamoto T., et al. Characteristic elevation of matrix metalloproteinase activity in idiopathic interstitial pneumonias. Am J Respir Crit Care Med. 2000; 162(5): 1949–1956. DOI: 10.1164/ajrccm.162.5.9906096
  48. Hong J.-S., Greenlee K.J., Pitchumani R., et al. Dual protective mechanisms of matrix metalloproteinases 2 and 9 in immune defense against Streptococcus pneumoniae. J Immunol. 2011; 186(11): 6427–6436. DOI: 10.4049/jimmunol.1003449
  49. Deotare U., Al-Dawsari G., Couban S., et al. G-CSF-primed bone marrow as a source of stem cells for allografting: revisiting the concept. Bone Marrow Transplant. 2015; 50: 1150. DOI: 10.1038/bmt.2015.80
  50. Becher B., Tugues S., Greter M. GM-CSF: From Growth Factor to Central Mediator of Tissue Inflammation. Immunity. 2016; 45(5): 963–973. DOI: 10.1016/j.immuni.2016.10.026
  51. Ishikawa H., Fukui T., Ino S., et al. Influenza virus infection causes neutrophil dysfunction through reduced G-CSF production and an increased risk of secondary bacteria infection in the lung. Virology. 2016; 499: 23–29. DOI: 10.1016/j.virol.2016.08.025
  52. Subramaniam R., Barnes P.F., Fletcher K., et al. Protecting against post-influenza bacterial pneumonia by increasing phagocyte recruitment and ROS production. J Infect Dis. 2014; 209(11): 1827–1836. DOI: 10.1093/infdis/jit830
  53. Ley K. Weird and weirder: How circulating chemokines coax neutrophils to the lung. Am J Physiol — Lung Cell Mol Physiol. 2004; 286(3): 463–464. DOI: 10.1152/ajplung.00386.2003
  54. Gotsch F., Romero R., Friel L., et al. CXCL10/IP-10: a missing link between inflammation and anti-angiogenesis in preeclampsia? J Matern neonatal Med Off J Eur Assoc Perinat Med Fed Asia Ocean Perinat Soc Int Soc Perinat Obstet. 2007; 20(11): 777–792. DOI: 10.1080/14767050701483298
  55. Baba T., Mukaida N. Role of macrophage inflammatory protein (MIP)-1α/CCL3 in leukemogenesis. Mol Cell Oncol. 2014; 1(1): DOI: 10.4161/mco.29899
  56. Menten P., Wuyts A., Van Damme J. Macrophage inflammatory protein-1. Cytokine Growth Factor Rev. 2002; 13(6): 455–481.
  57. Zeng X., Moore T.A., Newstead M.W., et al. Interferon-inducible protein 10, but not monokine induced by gamma interferon, promotes protective type 1 immunity in murine Klebsiella pneumoniae pneumonia. Infect Immun. 2005; 73(12): 8226–8236. DOI: 10.1128/IAI.73.12.8226-8236.2005
  58. Sun X., Jones H.P., Hodge L.M., et al. Cytokine and chemokine transcription profile during Mycoplasma pulmonis infection in susceptible and resistant strains of mice: macrophage inflammatory protein 1beta (CCL4) and monocyte chemoattractant protein 2 (CCL8) and accumulation of CCR5+ Th cells. Infect Immun. 2006; 74(10): 5943–5954. DOI: 10.1128/IAI.00082-06
  59. Jia R., Yang J., Cui Y., et al. Gene expression analysis for pneumonia caused by Gram-positive bacterial infection. Exp Ther Med. 2018; 15(4): 3989–3996. DOI: 10.3892/etm.2018.5904
  60. Dayer J.-M., Oliviero F., Punzi L. A Brief History of IL-1 and IL-1 Ra in Rheumatology. Front Pharmacol. 2017; 8: DOI: 10.3389/fphar.2017.00293
  61. Walter M.R. The molecular basis of IL-10 function: from receptor structure to the onset of signaling. Curr Top Microbiol Immunol. 2014; 380: 191–212. DOI: 10.1007/978-3-662-43492-5_9
  62. Peñaloza H.F., Noguera L.P., Riedel C.A., et al. Expanding the Current Knowledge About the Role of Interleukin-10 to Major Concerning Bacteria. Front Microbiol. 2018; 9: 2047. DOI: 10.3389/fmicb.2018.02047
  63. Grover V., Pantelidis P., Soni N., et al. A biomarker panel (Bioscore) incorporating monocytic surface and soluble TREM-1 has high discriminative value for ventilator-associated pneumonia: a prospective observational study. PLoS One. 2014; 9(10): DOI: 10.1371/journal.pone.0109686
  64. Hellyer T.P., Anderson N.H., Parker J., et al. Effectiveness of biomarker-based exclusion of ventilator-acquired pneumonia to reduce antibiotic use (VAPrapid-2): study protocol for a randomised controlled trial. Trials. 2016; 17(1): 318. DOI: 10.1186/s13063-016-1442-x
  65. Zobel K., Martus P., Pletz M.W., et al. Interleukin 6, lipopolysaccharide-binding protein and interleukin 10 in the prediction of risk and etiologic patterns in patients with community-acquired pneumonia: results from the German competence network CAPNETZ. BMC Pulm Med. 2012; 12: 6. DOI: 10.1186/1471-2466-12-6
  66. Franz A.R., Steinbach G., Kron M., et al. Reduction of unnecessary antibiotic therapy in newborn infants using interleukin-8 and C-reactive protein as markers of bacterial infections. Pediatrics. 1999; 104(3 Pt 1): 447–453. DOI: 10.1542/peds.104.3.447
  67. Weitkamp J.-H., Reinsberg J., Bartmann P. Interleukin-8 (IL-8) preferable to IL-6 as a marker for clinical infection. Clin Diagn Lab Immunol. 2002; 9(6): DOI: 10.1128/cdli.9.6.1401.2002
  68. Ding S., Wang X., Chen W., et al. Decreased Interleukin-10 Responses in Children with Severe Mycoplasma pneumoniae Pneumonia. PLoS One. 2016; 11(1): e0146397. DOI: 10.1371/journal.pone.0146397
  69. Conway Morris A., Kefala K., Wilkinson T.S., et al. Diagnostic importance of pulmonary interleukin-1beta and interleukin-8 in ventilator-associated pneumonia. Thorax. 2010; 65(3): 201–207. DOI: 10.1136/thx.2009.122291
  70. Liu M., Li H., Xue C.X., et al. Differences in inflammatory marker patterns for adult community-acquired pneumonia patients induced by different pathogens. Clin Respir J. 2018; 12(3): 974–985. DOI: 10.1111/crj.12614
  71. Bircan H.A., Cakir M., Yilmazer Kapulu I., et al. Elevated serum matrix metalloproteinase-2 and -9 and their correlations with severity of disease in patients with community-acquired pneumonia. Turkish J Med Sci. 2015; 45(3): 593–599. DOI: 10.3906/sag-1402-51
  72. Puljiz I., Markotic A., Cvetko Krajinovic L., et al. Mycoplasma pneumoniae in adult community-acquired pneumonia increases matrix metalloproteinase-9 serum level and induces its gene expression in peripheral blood mononuclear cells. Med Sci Monit. 2012; 18(8): CR500–505.
  73. Martin-Loeches I., Bos L.D., Povoa P., et al. Tumor necrosis factor receptor 1 (TNFRI) for ventilator-associated pneumonia diagnosis by cytokine multiplex analysis. Intensive care Med Exp. 2015; 3(1): 26. DOI: 10.1186/s40635-015-0062-1
  74. Overgaard C.E., Schlingmann B., Dorsainvil White S., et al. The relative balance of GM-CSF and TGF-beta1 regulates lung epithelial barrier function. Am J Physiol Lung Cell Mol Physiol. 2015; 308(12): L1212–1223. DOI: 10.1152/ajplung.00042.2014
  75. Relster M.M., Holm A., Pedersen C. Plasma cytokines eotaxin, MIP-1alpha, MCP-4, and vascular endothelial growth factor in acute lower respiratory tract infection. APMIS. 2017; 125(2): 148–156. DOI: 10.1111/apm.12636
  76. Salehifar E., Tavakolian Arjmand S., Aliyali M., et al. Role of C-reactive Protein and Tumor Necrosis Factor-Alpha in Differentiating between Ventilator-Associated Pneumonia and Systemic Inflammatory Response Syndrome without Infectious Etiology. Tanaffos. 2016; 15(4): 205–212.
  77. Bacci M.R., Leme R.C.P., Zing N.P.C., et al. IL-6 and TNF-alpha serum levels are associated with early death in community-acquired pneumonia patients. Brazilian J Med Biol Res = Rev Bras Pesqui medicas e Biol. 2015; 48(5): 427–432. DOI: 10.1590/1414-431X20144402
  78. Lorenzo M.-J., Moret I., Sarria B., et al. Lung inflammatory pattern and antibiotic treatment in pneumonia. Respir Res. 2015; 16(1): 15. DOI: 10.1186/s12931-015-0165-y
  79. Zhao L., Wang L., Zhang X., et al. Reduced levels of interleukin1 receptor antagonist act as a marker for pneumonia in the elderly. Mol Med Rep. 2014; 10(2): 959–964. DOI: 10.3892/mmr.2014.2284
  80. Endeman H., Meijvis S.C.A., Rijkers G.T., et al. Systemic cytokine response in patients with community-acquired pneumonia. Eur Respir J. 2011; 37(6): 1431–1438. DOI: 10.1183/09031936.00074410
Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.

Copyright (c) 2021 ANNALS OF CRITICAL CARE


Download data is not yet available.