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Home > Coronavirus > Cytokine Release Syndrome

Cytokine Release Syndrome

Cytokines are small proteins produced in the body to mediate cell signaling. Most, but not all, cytokines are involved in regulation of the immune system. Cytokine Release Syndrome is characterized by an immune over-response, where the majority of the damage done to the host is due to the immune system rather than the pathogen. This damage is mediated by excessive recruitment of immune cells to the sites of infection and overproduction of inflammatory cytokines, which lead to tissue damage and hypotensive shock.

Both severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome CoV (MERS-CoV) cause a severe and highly lethal respiratory disease in humans. This disease is characterized by a prominent pro-inflammatory response and mediated by release of cytokines. (Chan, J. F, 2015)

COVID-19 induces pro-inflammatory generation and secretion of cytokines, including IL-1b and IL-6, via the toll like receptors (TLR). This causes the production of active mature IL-1b, which is a mediator of lung inflammation, fever and fibrosis. Anti-inflammatory cytokines, such as IL1-Ra, IL-37 or IL-38 could potentially provide relief in both systemic inflammation and fever occurring after infection (Conti. P, 2020).

Cytokines involved in infection from SARS-CoV-2 include IL-1, IL-1B, IL-2, IL-2R, IL-2RG, IL-6, IL-8, 1L-10, IL-17D, IL-18, IFNGR1, JAK2, NLRP3, TNFA, MCP1 and MIP1A (GCSF). (C. Huang, 2020)


Interleukin-1 Alpha (IL-1A)

IL-1A is a pro-inflammatory cytokine and an important mediator of local and systemic inflammation. Excessive IL-1A release during viral infections can cause lung and tissue inflammation, fever and fibrosis. IL-1 suppression has found to be effective in many inflammatory diseases, including rheumatoid arthritis

Interleukin-1 Beta (IL-1B)

IL-1B is a potent proinflammatory cytokine. Initially discovered as the major endogenous pyrogen, it induces prostaglandin synthesis, neutrophil influx and activation, T-cell activation and cytokine production, B-cell activation and antibody production, and fibroblast proliferation and collagen production. It promotes differentiation of the TH17 subset of T-cells.

Interleukin-2 (IL-2)

Produced by T-cells in response to antigenic or mitogenic stimulation, this protein is required for T-cell proliferation and many other activities crucial to regulation of the immune response. It can stimulate B-cells, monocytes, lymphokine-activated killer cells, natural killer cells, and glioma cells.

Interleukin-2 Receptor (IL-2R)

The increased expression of IL-2R and IL-6 in serum is expected to predict increased severity of 2019-nCoV pneumonia and a poorer patient prognosis (Chen, L, et al, 2020).

Interleukin-2 Receptor Gamma (IL-2RG)

Cytokine receptor common subunit gamma is a common subunit for the receptors for a variety of interleukins. Probably in association with IL15RA, it is involved in the stimulation of neutrophil phagocytosis by IL15.

Interleukin-6 (IL-6)

IL-6 is a cytokine with a wide variety of biological functions. It is a potent inducer of the acute phase response, plays an essential role in the final differentiation of B-cells into immunoglobulin-secreting cells, and is involved in lymphocyte and monocyte differentiation. IL-6 acts on B-cells, T-cells, hepatocytes, hematopoietic progenitor cells, and cells of the CNS. It is also required for the generation of TH17 cells.

Increased expression of IL-2R, D-Dimer, and IL-6 in serum was associated with increased severity of 2019-nCoV pneumonia and poorer patient prognosis. (Russell Beth, 2020) (Chen. L, et al)

Interleukin-8 (IL-8)

IL-8 is a chemotactic factor that attracts neutrophils, basophils, and T-cells, but not monocytes. It is also involved in neutrophil activation. IL-8 is released from several cell types in response to an inflammatory stimulus.

Interleukin-10 (IL-10)

IL-10 inhibits the synthesis of a number of cytokines, including IFN-gamma, IL-2, IL-3, TNF and GM-CSF. IL-10 is produced by activated macrophages and by helper T-cells.

Interleukin-17D (IL-17D)

IL-17D induces expression of IL6, CXCL8/IL8, and CSF2/GM-CSF from endothelial cells.

Interleukin-17A (IL-17A)

IL-17A is part of the ligand for IL17RA and IL17RC. The heterodimer formed by IL17A and IL17F is the ligand for the heterodimeric complex formed by IL17RA and IL17RC. It is involved in inducing stromal cells to produce proinflammatory and hematopoietic cytokines.

Interleukin-18 (IL-18)

IL-18 augments natural killer cell activity in spleen cells and stimulates interferon gamma production in T-helper type I (TH1) cells. IL-18 belongs to the IL-1 family.

Interferon Gamma Receptor 1 (IFNGR1)

IFNGR1 associates with IFNGR2 to form the receptor for interferon gamma (IFNG). Ligand binding stimulates activation of the JAK/STAT signaling pathway.

Tyrosine-Protein Kinase JAK2

JAK2 is a non-receptor tyrosine kinase involved in various processes, such as cell growth, development, differentiation, and histone modification. The JAK2 pathway mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, JAK2 plays a pivotal role in signal transduction via its association with type I receptors, such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), and thrombopoietin (THPO); or type II receptors, including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins. JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation, which may lead to the hypertension observed in some COVID-19 patients. (Guilluy C, 2010)

NACHT, LRR and PYD domains-containing protein 3(NLRP3)

As the sensor component of the NLRP3 inflammasome, NLRP3 plays a crucial role in innate immunity and inflammation. The SARS-CoV open reading frame 3a (ORF3a) accessory protein activates the NLRP3 inflammasome by promoting TNF receptor-associated factor 3 (TRAF3)-mediated ubiquitination of apoptosis-associated speck-like protein, containing a caspase recruitment domain (ASC). Since the orf3a domain in SARS-COV-2 is approximately 73% similar to SARS-CoV, it is likely to be involved in a similar mechanism (Kam-Leung Siu, 2019).

Tumor Necrosis Factor-alpha (TNFa)

The TNF family of receptors and cytokines is very large and this family is frequently targeted by drugs. TNFa is a pro-inflammatory cytokine involved in autoimmune and immune-mediated disorders such as rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, psoriasis, hidradenitis suppurativa and refractory asthma. TNFa inhibitors act by suppressing the physiologic response to TNFa.

Inhibition of TNFa can be achieved with a monoclonal antibody, such as Infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia) and golimumab (Simponi), or with a receptor fusion protein, etanercept (Enbrel). Low-dose prednisolone and tacrolimus may have beneficial impacts on COVID-19. (Russell Beth, 2020)

C-C motif chemokine 2 (MCP1/CCL2)

C-C motif chemokine 2 (MCP1/CCL2) is a chemotactic factor that attracts monocytes and basophils but not neutrophils or eosinophils. CCL2 augments monocyte anti-tumor activity, and has been implicated in the pathogenesis of diseases characterized by monocytic infiltrates, like psoriasis, rheumatoid arthritis, and atherosclerosis.

Granulocyte Colony-Stimulating Factor (MIP1A/GCSF)

Granulocyte/macrophage colony-stimulating factors are cytokines that act during hematopoiesis by controlling the production, differentiation, and function of granulocytes,monocytes, and macrophages. GCSF induces granulocytes and belongs to the IL-6 superfamily.


References:

  • Chan, J. F., Lau, S. K., To, K. K., Cheng, V. C., Woo, P. C., & Yuen, K. Y. (2015). Middle East respiratory syndrome coronavirus: another zoonotic betacoronavirus causing SARS-like disease. Clinical Microbiology Reviews, 28(2), 465–522.
  • Chen, L., Liu, H. G., Liu, W., Liu, J., Liu, K., Shang, J., Deng, Y., & Wei, S. (2020). Zhonghua jie he he hu xi za zhi = Zhonghua jiehe he huxi zazhi = Chinese Journal of Tuberculosis and Respiratory Diseases, 43(0), E005. Advance online publication. https://doi.org/10.3760.
  • Conti, P., Ronconi, G., Caraffa, A., Gallenga, C. E., Ross, R., Frydas, I., & Kritas, S. K. (2020). Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. Journal of Biological Regulators and Homeostatic Agents, 34(2), 1. Advance online publication. https://doi.org/10.23812/CONTI-E.
  • Guilluy, C., Brégeon, J., Toumaniantz, G., Rolli-Derkinderen, M., Retailleau, K., Loufrani, L., Henrion, D., Scalbert, E., Bril, A., Torres, R. M., Offermanns, S., Pacaud, P., & Loirand, G. (2010). The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure. Nature Medicine, 16(2), 183–190.
  • Huang, C., Wang, Y., Li, X., Ren, L., Zhao, J., Hu, Y., Zhang, L., Fan, G., Xu, J., Gu, X., Cheng, Z., Yu, T., Xia, J., Wei, Y., Wu, W., Xie, X., Yin, W., Li, H., Liu, M., Xiao, Y., … Cao, B. (2020). Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet (London, England), 395(10223), 497–506.
  • Kanayama, N., Kajiwara, Y., Goto, J., el Maradny, E., Maehara, K., Andou, K., & Terao, T. (1995). Inactivation of interleukin-8 by aminopeptidase N (CD13). Journal of Leukocyte Biology, 57(1), 129–134.
  • Russell, B., Moss, C., George, G., Santaolalla, A., Cope, A., Papa, S., & Van Hemelrijck, M. (2020). Associations between immune-suppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence. Ecancermedicalscience, 14, 1022.
  • Siu, K. L., Yuen, K. S., Castaño-Rodriguez, C., Ye, Z. W., Yeung, M. L., Fung, S. Y., Yuan, S., Chan, C. P., Yuen, K. Y., Enjuanes, L., & Jin, D. Y. (2019). Severe acute respiratory syndrome coronavirus ORF3a protein activates the NLRP3 inflammasome by promoting TRAF3-dependent ubiquitination of ASC. FASEB journal: Official Publication of the Federation of American Societies for Experimental Biology, 33(8), 8865–8877.
  • Szklarczyk, D., Morris, J. H., Cook, H., Kuhn, M., Wyder, S., Simonovic, M., Santos, A., Doncheva, N. T., Roth, A., Bork, P., Jensen, L. J., & von Mering, C. (2017). The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Research, 45(D1), D362–D368.
  • Wu, D., & Yang, X. O. (2020). TH17 responses in cytokine storm of COVID-19: An emerging target of JAK2 inhibitor Fedratinib. Journal of Microbiology, Immunology, and Infection = Wei mian yu gan ran za zhi, S1684-1182(20)30065-7.

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IL-1B / IL-1 Beta Antibody - Human Uterus, Vessel: Formalin-Fixed, Paraffin-Embedded (FFPE)
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Rabbit Polyclonal (IgG) to Human IL-1B / IL-1 Beta
Mouse, Human
IHC-P, WB
Unconjugated
50µl   $425.00
IL-1B / IL-1 Beta Antibody - Immunohistochemistry of Human IL1 beta antibody. Tissue: medullary lymph node. Fixation: formalin fixed paraffin embedded. Antigen retrieval: user optimized. Primary antibody: Human IL1 beta antibody. Secondary antibody: Peroxidase goat anti-rabbit at 1:10,000 for 45 min at RT. Localization: cytoplasm. Staining: Close up of medullary lymph node: positive staining in the cytoplasm of circulating macrophages. Neg Ctr (far right) of normal rabbit IgG with pH 6.2 at 40X.
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Rabbit Polyclonal (IgG) to Human IL-1B / IL-1 Beta
Dog, Human, Primate
ELISA, Flo, IF, IHC, IHC-Fr, IHC-P, IP, Neut, RIA, WB
Unconjugated
1mg   2mg/ml   $1,140.00
IL-1B / IL-1 Beta Antibody - Western Blot (non-reducing) of IL1B / IL-1 Beta antibody. This image was taken for the unconjugated form of this product. Other forms have not been tested.
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Rabbit Polyclonal to Rat IL-1B / IL-1 Beta
Rat
ELISA, WB
Unconjugated
50µg   $285.00; 100µg   $325.00
IL-1B / IL-1 Beta Antibody - Western Blot (non-reducing) of IL1B / IL-1 Beta antibody. This image was taken for the unconjugated form of this product. Other forms have not been tested.
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Rabbit Polyclonal to Rat IL-1B / IL-1 Beta
Rat
ELISA, WB
Biotin Conjugated
25µg   $285.00; 50µg   $325.00
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Rabbit Polyclonal (IgG) to Sheep IL-1B / IL-1 Beta
Sheep
ELISA, WB
Unconjugated, Serum
0.1ml   $475.00
IL-1B / IL-1 Beta Antibody - IHC of paraffin-embedded muscle tissues using IL1B mouse monoclonal antibody with DAB staining.
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Mouse Monoclonal [clone 3A6] (IgG1) to Human IL-1B / IL-1 Beta
Human
ELISA, IF, IHC, IHC-P, WB
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100µl   $365.00
IL-1B / IL-1 Beta Antibody - IHC of paraffin-embedded Adenocarcinoma of Human endometrium tissue using anti-IL1B mouse monoclonal antibody.
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Mouse Monoclonal [clone OTI3E1] (IgG1) to Human IL-1B / IL-1 Beta
Human
IF, IHC, IHC-P, WB
Unconjugated
100µl   1mg/ml   $345.00
IL-1B / IL-1 Beta Antibody - Formalin-fixed and paraffin-embedded human lung carcinoma with IL1B Antibody , which was peroxidase-conjugated to the secondary antibody, followed by DAB staining. This data demonstrates the use of this antibody for immunohistochemistry; clinical relevance has not been evaluated.
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Rabbit Polyclonal to Human IL-1B / IL-1 Beta
Human
Flo, IHC, IHC-P, WB
Unconjugated
400µl   $325.00
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Mouse Monoclonal [clone ID4] (IgG1) to Sheep IL-1B / IL-1 Beta
Goat, Sheep, Bovine
ELISA, Flo, IHC, IHC-Fr
Unconjugated
50µg   $365.00; 250µg   $920.00
IL-1B / IL-1 Beta Antibody - Western Blot (non-reducing) of IL1B / IL-1 Beta antibody. This image was taken for the unconjugated form of this product. Other forms have not been tested.
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Rabbit Polyclonal to Mouse IL-1B / IL-1 Beta
Mouse
ELISA, WB
Unconjugated
50µg   $285.00; 100µg   $325.00
IL-1B / IL-1 Beta Antibody - Human peripheral blood mononuclear cells were stimulated with LPS in the presence of Brefeldin A for 4 hours. The cells were surface stained with FITC anti-human CD14 and intracellularly stained with PE anti-human IL-1b.
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Mouse Monoclonal [clone CRM56] (IgG1) to Human IL-1B / IL-1 Beta
Human
ELISA, Flo, Neut
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50µg   0.5mg/ml   $225.00; 500µg   0.5mg/ml   $335.00
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Mouse Monoclonal [clone DF8] (IgG1) to Pig IL-1B / IL-1 Beta
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WB
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250µg   $605.00; 500µg   $1,095.00
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Rabbit Polyclonal to Mouse IL-1B / IL-1 Beta
Mouse
ELISA, Neut, WB
Unconjugated
30µg   0.5mg/ml   $245.00; 100µg   0.5mg/ml   $475.00
IL-1B / IL-1 Beta Antibody - Western blot of IL-1beta antibody
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Rabbit Polyclonal (IgG) to Human IL-1B / IL-1 Beta
Mouse, Rat, Human
ELISA, WB
Unconjugated
50µl   1mg/ml   $235.00; 100µl   1mg/ml   $265.00; 200µl   1mg/ml   $335.00
IL-1B / IL-1 Beta Antibody - Western blot of recombinant IL1B.  This image was taken for the unconjugated form of this product. Other forms have not been tested.
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Guinea pig Polyclonal to Rabbit IL-1B / IL-1 Beta
Rabbit
WB
Unconjugated
100µl   0.5mg/ml   $255.00; 200µl   0.5mg/ml   $295.00; 500µl   0.5mg/ml   $435.00; 1ml   0.5mg/ml   $515.00
IL-1B / IL-1 Beta Antibody - Immunofluorescence of monoclonal antibody to IL1B on HeLa cell . [antibody concentration 10 ug/ml]
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Mouse Monoclonal [clone 2A8] (IgG2b,k) to Human IL-1B / IL-1 Beta
Human
ELISA, IF, IP, WB
Unconjugated
100µg   $365.00
IL-1B / IL-1 Beta Antibody - Western blot analysis of IL-1 beta expression in HeLa (A); SHSY5Y (B); mouse liver (C) whole cell lysates.
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Rabbit Polyclonal to Human IL-1B / IL-1 Beta
Rabbit, Mouse, Rat, Human, Monkey
WB
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100µl   1mg/ml   $275.00
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Goat Polyclonal (IgG) to Human IL-1B / IL-1 Beta
Human
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Biotin Conjugated
50µg   $890.00
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Rabbit Polyclonal to Human IL-1B / IL-1 Beta
Dog, Human, Primate
ELISA, Flo, IF, IHC, IP, Neut, RIA, WB
Unconjugated
1ml   77mg/ml   $1,140.00
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Mouse Monoclonal [clone DF8] (IgG1) to Pig IL-1B / IL-1 Beta
Pig
WB
Unconjugated, Preservative Free
0.5mg   $740.00
IL-1B / IL-1 Beta Antibody - Anti-Human IL-1beta Antibody - Western Blot. This antibody is primarily directed against mature, 17000 MW human IL-1beta and is useful in determining its presence in various assays.
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Rabbit Polyclonal (IgG) to Human IL-1B / IL-1 Beta
Dog, Human, Primate
ELISA, Flo, IF, IHC, IP, Neut, RIA, WB
Unconjugated
100µg   1mg/ml   $425.00
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Mouse Monoclonal [clone CRM57] (IgG2b) to Human IL-1B / IL-1 Beta
Human
ELISA
Biotin Conjugated
50µg   0.5mg/ml   $245.00; 500µg   $375.00
IL-1B / IL-1 Beta Antibody - Staining murine bone marrow-derived macrophages cells by IF/ICC. The samples were fixed with PFA and permeabilized in 0.1% Triton X-100, then blocked in 10% serum for 45 min at 25°C. The primary antibody was diluted at 1:200 and incubated with the sample for 1 hour at 37°C. An Alexa Fluor 594 conjugated goat anti-rabbit IgG (H+L) antibody, diluted at 1/600 was used as secondary antibody.
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Rabbit Polyclonal (IgG) to Human IL-1B / IL-1 Beta
Mouse, Rat, Human
ELISA, IF, IHC, WB
Unconjugated
100µl   1mg/ml   $325.00; 200µl   1mg/ml   $375.00
IL-1B / IL-1 Beta Antibody - Western Blot of Rabbit anti-Mouse IL-1ß Antibody Biotin Conjugated. Lane 1: Mouse IL-1ß Recombinant Protein. Load: 50 ng per lane. Primary antibody: Rabbit anti-Mouse IL-1ß Antibody Biotin Conjugated at 1:1,000 overnight at 4°C. Secondary antibody: HRP streptavidin secondary antibody at 1:40,000 for 30 min at RT.
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Rabbit Polyclonal (IgG) to Mouse IL-1B / IL-1 Beta
Mouse, Rat
ELISA, Flo, IF, IHC, IP, Neut, RIA, WB
Biotin Conjugated
100µg   1mg/ml   $425.00
IL-1B / IL-1 Beta Antibody - IL1 beta Antibody Peroxidase Conjugated Western Blot. Western Blot of Rabbit anti-Mouse IL-1 Beta Antibody Peroxidase Conjugated Lane 1: Mouse IL-1 Beta Load: 50 ng per lane Secondary antibody: IL1 beta Antibody Peroxidase Conjugated at 1:1000 for 30 min at RT Block: MB-070 for 30 min RT Predicted/Observed size: 18 kD, 18 kD. This image was taken for the unconjugated form of this product. Other forms have not been tested.
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Rabbit Polyclonal (IgG) to Mouse IL-1B / IL-1 Beta
Mouse, Rat
ELISA, Flo, IF, IHC, IP, Neut, RIA, WB
HRP Conjugated
100µg   1mg/ml   $425.00

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