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. 2023 Jun 26:156287. Online ahead of print. doi: 10.1016/j.cyto.2023.156287

Figure 2.

Figure 2

Role of main cytokines in Covid-19: Cytokines are immunomodulating agents that are fundamental mediators for establishing communication amongst the immune system cells. When required, cytokines are rapidly secreted from the innate as well as adaptive immune cells. The body requires a homeostatic balance of cytokine levels, which if perturbed (such as in case of Covid-19 infection) could harm the host system. IL-1β is generated by monocytes/macrophages, dendritic cells, etc and is one of the most important cytokines engaged in Covid-19 mediated CS. IL-1β encourages the synthesis of IL-6 and can induce the synthesis of cyclooxygenase and inducible nitric oxide synthase (iNOS). The nitric oxide produced by iNOS contributes to tissue damage during airway inflammation. IL-1β is also secreted during the activation of the Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome. IL-6 is expressed in different immune such as T and B cells, monocytes/macrophages, dendritic cells, and endothelial cells. The plasma concentration of IL-6 rises during Covid-19 infection. IL-6 encourages the differentiation and growth of B lymphocytes, increases platelet generation and induces reactive protein C (CRP) and fibrinogen secretion. Tumor necrosis factor (TNF-α) is a pro-inflammatory cytokine whose elevated plasma concentrations are in positive correlation with SARS-CoV-2 infection mediated CS. It can be produced by macrophages, T cells, and epithelial cells. TNF-α synthesis can be elicited by pathogen-associated molecular patterns and IL-1 through nuclear factor (NF-κB) activation. Under homeostasis conditions, TNF-α is related to B cells’ proliferation and differentiation. However, its unregulated levels are linked with several diseases, including pulmonary, cardiovascular, cancer, autoimmune, neurologic, and metabolic disorders. Interferon-gamma (IFN-γ) is an important pro-inflammatory cytokine implicated in immunity against intracellular pathogens and tumor control. IFN-γ is synthesized by natural killer and natural killer-T cells as part of the innate immune response. However, upon onset of adaptive immunity, IFN-γ can also be generated by the effector T cells, thus, linking the innate and adaptive immune responses. The combined increase in the levels of IFN-γ and TNF-α could activate the JAK/STAT1/IRF1 pathway, thereby inducing nitric oxide generation and ultimately resulting in caspase-8/FADD-interceded inflammatory cell death termed as PANoptosis.