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Cytokine Release Syndrome
Cytokines are small proteins produced in the body to mediate cell signaling and 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 an attack by the immune system rather than a direct cytotoxic effect by the pathogen. This systemic inflammatory response is mediated by the release (by immune cells) of inflammatory cytokines such as IFN-alpha, IFN-gamma, IL-1, IL-1 beta, IL-2, IL-2R, IL-6, IL-8, IL-10, IL-12, IL-17D, IL-18, IL-33, TNF-alpha, TGF-beta, and chemokines such as CCL2, CCL3, CCL5, CXCL8, CXCL9, and CXCL10. The overproduction of inflammatory cytokines leads to an attack on multiple organ systems resulting in ARDS, multi-organ failure, and hypotensive shock (Li, X., 2020; Huang, C., 2020). 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. These diseases are also characterized by a prominent pro-inflammatory response and mediated by release of cytokines (Chan, J.F., 2015).
Cytokine Release Syndrome Targets
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-1A suppression has been found to be effective in many inflammatory diseases, including rheumatoid arthritis.
All IL-1A ProductsInterleukin-1 Beta (IL-1B)
IL-1B is a potent pro-inflammatory 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.
All IL-1B ProductsInterleukin-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.
All IL-2 ProductsInterleukin-2 Receptor (IL-2R)
The increased expression of IL-2R and IL-6 in serum is expected to predict increased severity of COVID-19 pneumonia and a poorer patient prognosis (Chen, L., 2020).
All IL-2R ProductsInterleukin-2 Receptor Gamma (IL-2RG)
IL-2RG is a common subunit for the receptors for a variety of interleukins. Probably in association with IL-15RA, it is involved in the stimulation of neutrophil phagocytosis by IL-15.
All IL-2RG ProductsInterleukin-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 central nervous system (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, B., 2020) (Chen, L., 2020).
All IL-6 ProductsInterleukin-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.
All IL-8 ProductsInterleukin-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.
All IL-10 ProductsInterleukin-17D (IL-17D)
IL-17D induces expression of IL-6, CXCL8/IL-8, and CSF2/GM-CSF from endothelial cells.
All IL-17D ProductsInterleukin-17A (IL-17A)
IL-17A is part of the ligand for IL-17RA and IL-17RC. The heterodimer formed by IL-17A and IL-17F is the ligand for the heterodimeric complex formed by IL-17RA and IL-17RC. It is involved in inducing stromal cells to produce proinflammatory and hematopoietic cytokines.
All IL-17A ProductsInterleukin-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.
All IL-18 ProductsInterferon 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.
All IFNGR1 ProductsTyrosine-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 (TPOR); or with 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).
All JAK2 ProductsNACHT, 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 (Siu, K.L., 2019).
All NLRP3 ProductsTumor 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 B., 2020).
All TNFa ProductsC-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.
All MCP1/CCL2 ProductsGranulocyte 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.
All MIP1A/GCSF ProductsReferences
- 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.
- 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.
- 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.
All Cytokine Release Syndrome Products
