- Cytokines of the interleukin-6 (IL-6) family are important soluble mediators with crucial roles in developmental processes, tissue homeostasis, regeneration, and immune cell differentiation. Overshooting activities of IL-6 and other cytokines are found in all inflammatory diseases, making them attractive therapeutic targets for the treatment of patients with rheumatoid arthritis or inflammatory bowel disease. Multiple mechanisms exist that control cytokine activity and prevent excessive cytokine signaling under normal conditions. In this review, we summarize how the biology of IL-6 family cytokines is regulated by glycosylation, a process in which carbohydrate chains are covalently linked to protein molecules. The attached carbohydrates, which are generated and modified by enzymes located in the endoplasmic reticulum and/or the Golgi apparatus, can display huge structural diversity and are linked either via asparagine (N-glycans), serine and threonine (O-glycans), or tryptophanCytokines of the interleukin-6 (IL-6) family are important soluble mediators with crucial roles in developmental processes, tissue homeostasis, regeneration, and immune cell differentiation. Overshooting activities of IL-6 and other cytokines are found in all inflammatory diseases, making them attractive therapeutic targets for the treatment of patients with rheumatoid arthritis or inflammatory bowel disease. Multiple mechanisms exist that control cytokine activity and prevent excessive cytokine signaling under normal conditions. In this review, we summarize how the biology of IL-6 family cytokines is regulated by glycosylation, a process in which carbohydrate chains are covalently linked to protein molecules. The attached carbohydrates, which are generated and modified by enzymes located in the endoplasmic reticulum and/or the Golgi apparatus, can display huge structural diversity and are linked either via asparagine (N-glycans), serine and threonine (O-glycans), or tryptophan residues (C-glycans). We describe how glycosylation affects synthesis, receptor binding, signaling and plasma half-life of the cytokines and protein stability, transport to the cell surface, ligand binding, proteolysis, internalization, and recycling of their receptors. Finally, we discuss how knowledge about glycosylation can be used for the design of novel therapeutics targeting IL-6 family cytokines or their receptors.…
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