Biochem. Soc. Trans (2006) 34, 461-464 - H. Lortat-Jacob - Cytokine--Proteoglycan Interactions

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Biochemical Society Transactions (2006) 34, (461–464) (Printed in Great Britain)

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Interferon and heparan sulphate

H. Lortat-Jacob¹

Institut de Biologie Structurale UMR 5075 CEA-CNRS-UJF, 41 rue Jules Horowitz, 38027 Grenoble Cedex 1, France

Key words: glycoconjugate, heparan sulphate, inhibition, interferon-g, mimetic, signalling receptor.

Abbreviations used: HS, heparan sulphate; IFN, interferon; JAK, Janus kinase; NK cell, natural killer cell; STAT, signal transducer and activator of transcription.

In 1954, substances that protected cells from viral infection were discovered and named IFN (interferon). This family of cytokines, which were the first to be used in clinical therapy, is classified into type I and II IFNs. Type I mainly consists of IFNa and IFNb subtypes, which are structurally related and bind to a common receptor. IFNg, the sole type II IFN, is structurally unrelated, binds to a different receptor and, as a dimer, strongly interacts with HS (heparan sulphate). In addition to its antiviral activity, it modulates nearly all phases of immune and inflammatory responses. IFNg binding to HS controls the blood clearance, the subsequent tissue targeting and the local accumulation of the cytokine. It also regulates IFNg activity by a unique mechanism involving a controlled processing of the C-terminal peptide. The binding site encompasses an N-acetylated glucosamine-rich domain separating two highly sulphated sequences that each binds to one IFNg monomer. Based on this template, a set of glycoconjugate mimetics that would mimic the IFNg binding site has been synthesized. One of these molecules displays high affinity for the cytokine and inhibits binding to both HS and IFNgR (IFNg receptor), the cell-surface receptor. These results validate the HS structural determinants for IFNg recognition, and provide a new strategy to inhibit IFNg in a number of diseases in which the cytokine has been identified as a target.