Pro-Inflammatory Interleukins

Pro-inflammatory interleukins are a series of immune regulatory molecules (cytokines) and are involved in the up-regulation of inflammatory reactions. Various pro-inflammatory interleukins such as IL-1, IL-17 and IL-23 have been identified to be angiogenic, and increase EC migration, cord-like structure organization, and MMP production.

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Pro-Inflammatory Interleukins Function

IL-1, a pro-inflammatory interleukin that activates the inflammatory process, and its deregulated signaling causes devastating diseases manifested by severe acute or chronic inflammation. Specifically, both IL-1α and IL-1β are synthesized as precursor (proform) proteins with molecular weights of about 31 kDa, can be cleaved to smaller mature forms of 17 kDa and bind the cell surface receptor IL-1R1, and they trigger identical biological responses.

IL-6, is a cytokine not only involved in inflammation and infection responses but also in the regulation of metabolic, regenerative, and neural processes. IL-6 is a interleukin which possesses pro- and anti-inflammatory properties. It turns out that regenerative or anti-inflammatory activities of interleukin-6 are mediated by classic signaling whereas pro-inflammatory responses of interleukin-6 are rather mediated by trans-signaling. This is important since therapeutic blockade of interleukin-6 by the neutralizing anti-interleukin-6 receptor monoclonal antibody tocilizumab has recently been approved for the treatment of inflammatory diseases.

IL-12, a pro-inflammatory interleukin, is a heterodimeric cytokine produced mostly by phagocytic cells in response to bacteria, bacterial products, and intracellular parasites, and to some degree by B lymphocytes. IL-12 induces cytokine production, primarily of IFN-gamma, from NK and T cells, acts as a growth factor for activated NK and T cells, enhances the cytotoxic activity of NK cells, and favors cytotoxic T lymphocyte generation.

IL-17, commonly known as IL-17A, is a pro-inflammatory interleukin with multiple functions in the regulation of tissue inflammation. So far, six different IL-17, namely, IL-17A to F, have been described and are structurally homologous to each other. IL-17 has a key role in tissue neutrophil recruitment and helps the clearance of pathogens such as extracellular bacteria. IL-17 is produced by several cell types including activated T-cell subsets (CD4+, CD8+, CD4− CD8−, γδT cells), natural killer cells, and neutrophils. The pathogenic role of IL-17 has been observed in EAE, CIA, inflammatory bowel disease (IBD), and SLE. IL-17 facilitates T-cell activation and infiltration into tissues by upregulating the expression of intercellular adhesion molecule-1 (ICAM-1).

IL-18, an IL-1 family cytokine, is a pleiotropic immune regulator. IL-18 plays a strong pro-inflammatory role by inducing interferon (IFN)-γ. The IL18 gene is located on chromosome 9 in mice and on chromosome 11 in humans. IL-18 is structurally similar to members of the IL-1 family of cytokines, especially IL-1β and IL-33.

IL-23, is a pro-inflammatory interleukin composed of two subunits, p19 and p40. The p40 subunit is shared with IL-12. IL-23 and IL-12 have different receptors and different effects. Whereas IL-12 induces development of Th1 cells, which produce interferon-γ, IL-23 is involved in differentiation of Th17 cells in a pro-inflammatory context and especially in the presence of TGF-β and IL-6. Inflammatory macrophages express IL-23R and are activated by IL-23 to produce IL-1, TNF-α, and IL-23 itself. These effects identify IL-23 as a central cytokine in autoimmunity and a highly promising treatment target for inflammatory diseases. IL-23 is found in the skin of patients with psoriasis, in the bowel wall of patients with chronic inflammatory bowel disease, and in synovial membrane of patients with rheumatoid arthritis. Ustekinumab, which inhibits IL-12 and IL-23 by blocking p40, has been found effective in cutaneous psoriasis and psoriatic arthritis, as well as in Crohn's disease.


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