COVID-19'U ANLAMAK: SİTOKİN ETKİSİNİN İMMÜNOPATOJENİK MEKANİZMALARI
Sitokin salınım sendromu (SSS) veya sitokin fırtınası,
SARS-CoV-2 tarafından başlatılabilen, bağışıklık
sisteminin orantısız tepkisinden kaynaklanan proinflamatuar
sitokinlerin aşırı üretiminin bir sonucudur.
SARS-CoV-2'nin neden olduğu COVID-19, sitokinlerle
korelasyon göstermektedir. SARS-CoV-2, yaygın
dağılım gösteren makrofajlar ve mast hücreleri sayesinde
IL-1 üretimini tetiklemektedir. IL-1 ise, IL-6 ve
TNF-α üretimlerini etkileme eğilimindedir. COVID-19
şiddetinin ilerlemesi, IL-6 gibi bazı sitokin düzeylerini
etkiler. IL-6, SSS oluşumundan başlıca sorumlu olan
sitokindir. SSS, COVID-19 ile ilgili komplikasyonların
ve COVID-19 ile ilişkili ölümlerin ana nedenidir. Bu
zamana kadar literatürde bildirilmiş verilere rağmen,
SARS-CoV-2 ve sitokinler arasındaki ilişki tam olarak
aydınlatılmış değildir. Bu derleme ile söz konusu ilişkinin
irdelenmesi amaçlamıştır. COVID-19 tedavisi sırasında
sitokinlerin hedeflenmesi, hastaların hayatta
kalma oranlarını artırma ve COVID-19 ile ilişkili ölümleri
azaltma potansiyelini taşımaktadır. COVID-19
hastalığında, sitokin salınım mekanizmalarına ve salınan
sitokinlerin etkilerine odaklanılmasının, özellikle
T lenfositler üzerindeki etkilerinin ve IFN-γ üretiminin
irdelenmesinin, hastalığın ölümcül etkilerini azaltmaya
yardımcı olabileceği düşünülmektedir.
COMPREHENDING COVID-19: IMMUNOPATHOGENIC MECHANISMS OF CYTOKINE ACTION
Cytokine release syndrome (CRS) or cytokine storm is
as a result of the excess production of pro-inflammatory
cytokines which is due to the disproportionate response
of the immune system which can be instigated by
SARS-CoV-2. COVID-19 which is caused by SARSCoV-
2 has a correlation with cytokines. SARSCoV-
2 instigates the production of IL-1 by ubiquitous
macrophages and mast cells. IL-1 tends to influence
the production of IL-6 and TNF-α. The progression
of COVID-19 severity influences the level of certain
cytokines such as IL-6. IL-6 is the cytokine chiefly
responsible for the occurrence of CRS. CRS is the
cause of COVID-19-related complications and the
main cause of COVID-19-related deaths. Despite the
data reported in the literature so far, the relationship
between SARS-CoV-2 and cytokines has not been fully
elucidated. The aim of the present review is to examine
the relationship in question. Targeting cytokines during
COVID-19 treatment has the potential to increase
patient survival and reduce COVID-19-related deaths.
It is concluded that focusing on the mechanisms of
cytokine release and the effects of released cytokines,
especially examining the effects on T lymphocytes
and IFN-γ production in COVID-19 disease, may help
reduce the lethal effects of the disease.
___
- 1. Li X, Geng M, Peng Y, Meng L. Lu Sh. Mol immune Pathog
diagnosis COVID-19, J Pharm Anal. 2020; 10(2):102–8.
- 2. Darif D, Hammi I, Kihel A, El Idrissi Saik I, Guessous F, Akarid
K. The pro-inflammatory cytokines in COVID-19 pathogenesis:
What goes wrong? Microb Pathog [Internet]. 2021; 153:104799.
Available from: https://www.sciencedirect.com/science/article/
pii/S0882401021000711
- 3. Kunnumakkara AB, Rana V, Parama D, Banik K, Girisa S, Sahu
H et al. COVID-19, cytokines, inflammation, and spices: How are
they related?. Life sciences. 2021 Feb 16:119201. https://www.
sciencedirect.com/science/article/pii/S0024320521001867
- 4. Karabacak P, Kırdemir P. COVID-19 hastalarında akut solunum
sıkıntısı sendromu yönetimi. Med J SDU. 2021 (özel sayı-
1): 51-56. DOI: 10.17343/sdutfd.901174.
- 5. Chan JF, Yuan S, Kok KH, To KK, Chu H, Yang J et al. A familial
cluster of pneumonia associated with the 2019 novel
coronavirus indicating person-to-person transmission: a study
of a family cluster. The lancet. 2020; 395(10223): 514-23. Available
from: https://www.sciencedirect.com/science/article/pii/
S0140673620301549
- 6. Dinarello CA. Impact of basic research on tomorrow’s medicine.
Chest. 2000; 118(2): 503–8.
- 7. dos Santos G, Delay L, Yaksh TL, Corr M. Neuraxial Cytokines
in Pain States. Front Immunol [Internet]. 2020; 10:3061.
Available from: https://www.frontiersin.org/article/10.3389/fimmu.
2019.03061
- 8. Fares J, Cordero A, Kanojia D, Lesniak MS. The Network of
Cytokines in Brain Metastases. Cancers (Basel). 2021; 13(1):
142.
- 9. Chauhan P, Nair A, Patidar A, Dandapat J, Sarkar A, Saha B. A
primer on cytokines. Cytokine. 2021 Feb; 155458.
- 10. Devrim T, Ekici H, Devrim AK, Sozmen M, Senol A, Bozkurt KM,
Duru O. Late effects of cutaneous 3-methylcholanthrene exposure
on DNA damage-related pleiotropic growth factors and
oxidative stress markers in mice. Bratisl Med J, 2020; 121(5):
325-330.
- 11. Berraondo P, Sanmamed MF, Ochoa MC, Etxeberria I, Aznar
MA, Pérez-Gracia JL et al. Cytokines in clinical cancer immunotherapy.
British journal of cancer. 2019; 120(1): 6-15.
- 12. Devrim T, Ataç F, Devrim AK, Balcı M. The concomitant use of
USP28 and p53 to predict the progression of urothelial carcinoma
of the bladder. Pathol Pract. 2020; 216(1): 152774.
- 13. Simpson S, Kaislasuo J, Guller S, Pal L. Thermal stability of
cytokines: A review. Cytokine. 2020; 125:154829.
- 14. Katze M. Into the eye of the cytokine storm. Microbiol Mol Biol
Rev. 2012; 76(1): 16–32.
- 15. Fares J, Fares MY, Khachfe HH, Salhab HA, Fares Y. Molecular
principles of metastasis: a hallmark of cancer revisited. Signal
Transduct Target Ther. 2020; 5(1): 1–17.
- 16. Rider P, Carmi Y, Cohen I. Biologics for targeting inflammatory
cytokines, clinical uses, and limitations. Int J Cell Biol. 2016;
2016: 9259646.
- 17. Shimabukuro-Vornhagen A, Gödel P, Subklewe M, Stemmler
HJ, Schlößer HA, Schlaak M et al. Cytokine release syndrome.
Journal for immunotherapy of cancer. 2018; 6(1):1-4.
- 18. Tang X, Wu C, Li X, Song Y, Yao X, Wu X et al. On the origin
and continuing evolution of SARS-CoV-2. National Science Review.
2020; 7(6): 1012-23.
- 19. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the
`Cytokine Storm' in COVID-19. J Infect. 2020; 80(6): 607-613.
- 20. Mahmud-Al-Rafat A, Asim MM, Taylor-Robinson AW, Majumder
A, Muktadir A, Muktadir H et al. A combinational approach to
restore cytokine balance and to inhibit virus growth may promote
patient recovery in severe COVID-19 cases. Cytokine, 2020;
15:155228.
- 21. Sallenave J-M, Guillot L. Innate immune signaling and proteolytic
pathways in the resolution or exacerbation of SARS-CoV-2
in Covid-19: key therapeutic targets? Front Immunol. 2020;11.
- 22. Conti P, Caraffa A, Gallenga CE, Ross R, Kritas SK, Frydas I et
al. Coronavirus-19 (SARS-CoV-2) induces acute severe lung
inflammation via IL-1 causing cytokine storm in COVID-19: a
promising inhibitory strategy. J Biol Regul Homeost Agents.
2020; 34(6): 1971-5.
- 23. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y et al. Clinical
features of patients infected with 2019 novel coronavirus in Wuhan,
China. The lancet. 2020; 395(10223): 497-506.
- 24. Ebihara N, Matsuda A, Nakamura S, Matsuda H, Murakami A.
Role of the IL-6 classic-and trans-signaling pathways in corneal
sterile inflammation and wound healing. Invest Ophthalmol Vis
Sci. 2011; 52(12): 8549–57.
- 25. Goncalves C-A, Sesterheim P. Serum amyloid A protein has
been undervalued as a biomarker of COVID-19. Diabetes Metab
Res Rev. 2020; 26:e3376.
- 26. Mosquera‐Sulbaran JA, Pedreañez A, Carrero Y, Callejas D.
C‐reactive protein as an effector molecule in Covid‐19 pathogenesis.
Rev Med Virol. 2021; e2221.
- 27. Chatterjee SK, Saha S, Munoz MNM. Molecular Pathogenesis,
Immunopathogenesis and Novel Therapeutic Strategy
Against COVID-19. Front Mol Biosci [Internet]. 2020; 7:196.
Available from: https://www.frontiersin.org/article/10.3389/
fmolb.2020.00196
- 28. Azkur AK, Akdis M, Azkur D, Sokolowska M, van de Veen W,
Brüggen MC et al. Immune response to SARS‐CoV‐2 and mechanisms
of immunopathological changes in COVID‐19. Allergy.
2020; 75(7): 1564-81.
- 29. Behrens EM, Koretzky GA. Cytokine storm syndrome: Looking
toward the precision medicine era. Arthritis Rheumatol. 2017;
69(6): 1135–43.
- 30. Coperchini F, Chiovato L, Croce L, Magri F, Rotondi M. The
cytokine storm in COVID-19: An overview of the involvement of
the chemokine/chemokine-receptor system. Cytokine Growth
Factor Rev. 2020; 53: 25–32.
- 31. Numbers K, Brodaty H. The effects of the COVID-19 pandemic
on people with dementia. Nat Rev Neurol. 2021; 1–2.
- 32. Chen G, Wu DI, Guo W, Cao Y, Huang D, Wang H et al. Clinical
and immunological features of severe and moderate coronavirus
disease 2019. The Journal of clinical investigation. 2020;
130(5): 2620-9.
- 33. Wang F, Hou H, Luo Y, Tang G, Wu S, Huang M et al. The
laboratory tests and host immunity of COVID-19 patients with
different severity of illness. JCI insight. 2020; 5(10): e137799.
- 34. Hadjadj J, Yatim N, Barnabei L, Corneau A, Boussier J, Smith
N et al. Impaired type I interferon activity and inflammatory
responses in severe COVID-19 patients. Science. 2020;
369(6504): 718-24.
- 35. Han H, Ma Q, Li C, Liu R, Zhao L, Wang W et al. Profiling serum
cytokines in COVID-19 patients reveals IL-6 and IL-10 are
disease severity predictors. Emerging microbes & infections.
2020; 9(1): 1123-30.
- 36. Gao Y, Li T, Han M, Li X, Wu D, Xu Y et al. Diagnostic utility
of clinical laboratory data determinations for patients with the
severe COVID‐19. Journal of medical virology. 2020; 92(7):
791-6.
- 37. Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors
of mortality due to COVID-19 based on an analysis of data of
150 patients from Wuhan, China. Intensive Care Med. 2020;
46(5): 846–8.
- 38. Liu Y, Zhang C, Huang F, Yang Y, Wang F, Yuan J et al. Elevated
plasma levels of selective cytokines in COVID-19 patients
reflect viral load and lung injury. National Science Review.
2020; 7(6): 1003-11.
- 39. Ryzhakov G, Lai CC, Blazek K, To K, Hussell T, Udalova I. IL-
17 Boosts Proinflammatory Outcome of Antiviral Response in
Human Cells. J Immunol [Internet]. 2011; 187(10): 5357–5362.
Available from: http://www.jimmunol.org/content/187/10/5357.
abstract
- 40. Hou W, Jin Y-H, Kang HS, Kim BS. Interleukin-6 (IL-6) and IL-
17 Synergistically Promote Viral Persistence by Inhibiting Cellular
Apoptosis and Cytotoxic T Cell Function. Perlman S, editor.
J Virol [Internet]. 2014; 88(15): 8479 LP – 8489. Available
from: http://jvi.asm.org/content/88/15/8479.abstract
- 41. Yang AP, Liu J ping, Tao W qiang, Li H ming. The diagnostic
and predictive role of NLR, d-NLR and PLR in COVID-19 patients.
Int Immunopharmacol [Internet]. 2020; 84: 106504. Available
from: https://doi.org/10.1016/j.intimp.2020.106504
- 42. Feng X, Li S, Sun Q, Zhu J, Chen B, Xiong M, et al. Immune-
inflammatory parameters in COVID-19 cases: A systematic
review and meta-analysis. Front Med. 2020; 7: 1–14.
- 43. Simadibrata DM, Pandhita BAW, Ananta ME, Tango T. Platelet-
to-lymphocyte ratio, a novel biomarker to predict the
severity of COVID-19 patients: A systematic review and meta-
analysis. J Intensive Care Soc. 2020; DOI: https://doi.
org/10.1177/1751143720969587
- 44. Kong J, Wang T, Di Z, Shi B, Yu X, Huang C, et al. Analysis of
hematological indexes of COVID-19 patients from fever clinics
in Suzhou, China. Int J Lab Hematol. 2020; 42(5): e204–6.
- 45. Xu X, Han M, Li T, Sun W, Wang D, Fu B et al. Effective treatment
of severe COVID-19 patients with tocilizumab. Proceedings
of the National Academy of Sciences. 2020; 117(20): 10970-
5. Available from: http://www.pnas.org/content/117/20/10970.
abstract
- 46. Ye Q, Wang B, Mao J. Elsevier has created a COVID-19 resource
centre with free information in English and Mandarin
on the novel coronavirus COVID- 19 . The COVID-19 resource
centre is hosted on Elsevier Connect , the company ’ s public
news and information. J Infect. 2020;(January).
- 47. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y et al. Epidemiological
and Clinical Characteristics of 99 Cases of 2019 Novel
Coronavirus Pneumonia in Wuhan, China: a descriptive study.
Lancet, 2020; 395 (10223): 507-513.