Johnson, Zoe and Kosco-Vilbois, Marie H. and Herren, Suzanne and Cirillo, Rocco and Muzio, Valeria and Zaratin, Paola and Carbonatto, Michela and Mack, Matthias and Smailbegovic, Amir and Rose, Mark and Lever, Rebecca and Page, Clive and Wells, Timothy N. C. and Proudfoot, Amanda E. I. (2004) Interference with heparin binding and oligomerization creates a novel anti-inflammatory strategy targeting the chemokine system. JOURNAL OF IMMUNOLOGY, 173 (9). pp. 5776-5785. ISSN 0022-1767, 1550-6606
Full text not available from this repository. (Request a copy)Abstract
A hallmark of autoimmunity and other chronic diseases is the overexpression of chemokines resulting in a detrimental local accumulation of proinflammatory immune cells. Chemokines play a pivotal role in cellular recruitment through interactions with both cell surface receptors and glycosaminoglycans (GAGs). Anti-inflammatory strategies aimed at neutralizing the chemokine system have to-date targeted inhibition of the receptor-ligand interaction with receptor antagonists. In this study, we describe a novel strategy to modulate the inflammatory process in vivo through mutation of the essential heparin-binding site of a proinflammatory chemokine, which abrogates the ability of the protein to form higher-order oligomers, but retains receptor activation. Using well-established protocols to induce inflammatory cell recruitment into the peritoneal cavity, bronchoalveolar air spaces, and CNS in mice, this non-GAG binding variant of RANTES/CCL5 designated [(44)AANA(47)]-RANTES demonstrated potent inhibitory capacity. Through a combination of techniques in vitro and in vivo, [(44)AANA(47)]-RANTES appears to act as a dominant-negative inhibitor for endogenous RANTES, thereby impairing cellular recruitment, not through a mechanism of desensitization. [(44)AANA(47)]-RANTES is unable to form higher-order oligomers (necessary for the biological activity of RANTES in vivo) and importantly forms nonfunctional heterodimers with the parent chemokine, RANTES. Therefore, although retaining receptor-binding capacity, altering the GAG-associated interactive site of a proinflammatory chemokine renders it a dominant-negative inhibitor, suggesting a powerful novel approach to generate disease-modifying anti-inflammatory reagents.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA; CENTRAL-NERVOUS-SYSTEM; HUMAN RANTES PROMOTER; CC CHEMOKINES; CYTOKINE EXPRESSION; MULTIPLE-SCLEROSIS; MICE; GLYCOSAMINOGLYCANS; SULFATE; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Innere Medizin II |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 23 Jun 2021 06:56 |
| Last Modified: | 23 Jun 2021 06:56 |
| URI: | https://pred.uni-regensburg.de/id/eprint/37002 |
Actions (login required)
 |
View Item |
