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*Substance via MeSH
Medline Plus Health Information
*Joint Disorders
*Osteoarthritis
The Journal of Immunology, 2002, 168: 2001-2010.
Copyright © 2002 by The American Association of Immunologists

Functional Genomic Analysis of Type II IL-1{beta} Decoy Receptor: Potential for Gene Therapy in Human Arthritis and Inflammation1

Mukundan G. Attur*, Mandar N. Dave*, Mary Y. Leung*, Christine Cipolletta*, Marcia Meseck§, Savio L. C. Woo§ and Ashok R. Amin2,*,{dagger},{ddagger}

* Laboratory for Functional and Pharmacogenomics, Hospital for Joint Diseases, New York, NY 10003; {dagger} Departments of Pathology and Medicine, New York University Medical Center, New York, NY 10016; {ddagger} Kaplan Cancer Center, New York, NY 10016; and § Institute for Gene Therapy and Molecular Medicine, Mt. Sinai School of Medicine, New York, NY 10029

Gene expression arrays show that human epithelial cells and human arthritis-affected cartilage lack detectable amounts of mRNA for IL-1 antagonizing molecules: IL-1Ra and IL-1RII, but constitutively express IL-1. Functional genomic analysis was performed by reconstituting human IL-1RII expression in various IL-1RII-deficient cell types to examine its antagonist role using gene therapy approaches. Adenovirus-expressing IL-1RII when transduced into human and bovine chondrocytes, human and rabbit synovial cells, human epithelial cells, and rodent fibroblasts expressed membrane IL-1RII and spontaneously released functional soluble IL-1RII. The IL-1RII+ (but not IL-1RII-) cells were resistant to IL-1{beta}-induced, NO, PGE2, IL-6, and IL-8 production or decreased proteoglycan synthesis. IL-1RII inhibited the function of IL-1 in chondrocytes and IL-1- and TNF-{alpha}-induced inflammatory mediators in human synovial and epithelial cells. IL-1RII+ chondrocytes were more resistant to induction of NO and PGE2 by IL-1{beta} compared with IL-1RII- cells incubated with a 10-fold (weight) excess of soluble type II IL-1R (sIL-1RII) protein. In cocultures, IL-1RII+ synovial cells released sIL-1RII, which in a paracrine fashion protected chondrocytes from the effects of IL-1{beta}. Furthermore, IL-1RII+ (but not IL-1RII-) chondrocytes when transplanted onto human osteoarthritis-affected cartilage in vitro, which showed spontaneous release of sIL-1RII for 20 days, inhibited the spontaneous production of NO and PGE2 in cartilage in ex vivo. In summary, reconstitution of IL-1RII in IL-1RII- cells using gene therapy approaches significantly protects cells against the autocrine and paracrine effects of IL-1 at the signaling and transcriptional levels.




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