Table 1.

Major functions of cytokines important to pro-inflammatory state

Cytokine	Function	References
IL-1β	Produced by monocytes/macrophages after PAMP or DAMP recognition by PRRs. Is a strong plasma marker of inflammation and induces vasodilation and immune cell extravasation. Is involved in the upregulation of the pleiotropic cytokine IL-6. The receptors for this cytokine could be found in different cell types, including B and T cells, monocyte, macrophage, PMN, DCs, and epithelial cells	[94, 95]
1L-2	Mainly produced by CD4 T cells, is an autocrine growth and activator factor for subpopulations of T lymphocytes. Is able to induce activation and proliferation of NK cells and activate B cells in presence of IL-4. The IL-2 production is closely regulated by costimulatory signals (such as IFN-a and IL-1), and antigen recognition. It is an important mediator of intercellular communication	[96, 97]
IL-6	Is produced by T cells, endothelial cells, fibroblasts, macrophages, and monocytes after infection or also in sterile inflammation. Contributes to the regulation of metabolism, liver regeneration, activation of T cells, differentiation of B cells. Is relevant for the regulation of acute-phase response due to the induction of proteins, including haptoglobin, C-reactive protein, serum amyloid A, fibrinogen, and α1-antitrypsin. The cell targets of this cytokine are B cell, T cell, basophil, neutrophil, and eosinophil	[98, 99]
IL-18	The active form is secreted by macrophages and DCs but also is constitutively expressed in PBMCs, macrophages, epidermal keratinocytes, epithelial cells, osteoblasts, and chondrocytes. Plays a critical role in the activation of hematopoietic cells and induction of IFN-γ Th1, Th2, DCs, and cytotoxic T cells. It is important to defense against intracellular pathogens through IFNγ production and induction of Th1-mediated immune response. Triggers a Th2 response after induces the production of IL-4 and IL-13 in basophils, mast cells, NK cells, and T cells	[100, 101]
TNF-α	It is indispensable for immunity and cell homeostasis. The active form is majority secreted by macrophages but can also be produced by keratinocytes, astrocytes, fibroblasts, and smooth muscle cells. Their effect is mediated by the receptors TNF-R1, universally expressed in all cell types, and TNF-R2, expressed on immune and endothelial cells. This cytokine regulates cell survival (apoptosis and necroptosis), activates vascular endothelium, promotes recruitment of immune cells, hyperalgesia, and tissue damage	[102, 103]
Type-I IFN	This family includes IFN-α, β, ε, κ, and ω. Are secreted for different types of infected cells. Activate innate immune response promoting cytokine production and NK cell activation. The signaling triggered by these cytokines leads to the expression of IFN-stimulated genes (ISGs) which encodes proteins important to restriction of replication and recognition of pathogens. I IFNs are extremely context-specific, depending on the tissue, the microbial stimulus, the receptor type for the nucleic acid sensor, and the subtype of IFN involved	[104, 105]
Type-II IFN	This family includes IFN-α, β, ε, κ, and ω. Are secreted for different types of infected cells. Activate innate immune response promoting cytokine production and NK cell activation. The signaling triggered by these cytokines leads to the expression of IFN-stimulated genes (ISGs) which encodes proteins important to restriction of replication and recognition of pathogens. I IFNs are extremely context-specific, depending on the tissue, the microbial stimulus, the receptor type for the nucleic acid sensor, and the subtype of IFN involved	[106, 107]