Cytokine and Protease Glycosylation as a Regulatory Mechanism in Inflammation and Autoimmunity

Summary

Cytokines are locally produced hormones that alert the innate and specific immune systems. Many cytokines induce, enhance and govern the traffic of leukocytes. An important mechanism in cell trafficking and migration through endothelial basement membranes and connective tissues is the cytokine-regulated production of matrix degrading proteases. The latter include the serine proteinases of plasminogen activation and metalloproteinases such as collagenases, stromelysins and gelatinases. Many cytokines and all known matrix proteinases are glycoproteins and thus occur as sets of glycoforms. The relation between structures and functions of these glycoproteins has already been probed extensively at the protein level but not yet at the carbohydrate level. Attached oligosaccharides target the cytokines and proteinases to specific cellular receptors and matrix binding sites. In addition, a number of cytokines possess lectin-like functions and may thus interact with carbohydrates of the host or parasites. These intermolecular interactions influence for instance the compartmentalisation, the cell- and tissue-specific distribution and the pharmacokinetics of cytokines and proteinases. Attempts were done to deduce structure-function rules for the intramolecular effects of carbohydrates on cytokines and matrix proteinases. The relatively voluminous N-linked sugars downmodulate the specific activities of enzymes and cytokines. Because in host stress reactions (infection, inflammation, trauma) N-linked glycosylation is less efficient, glycosylation may constitute an important regulatory mechanism in the cytokine network and in multi-enzyme cascades.