title: Functional genomic analysis of type II IL-1beta decoy receptor: potential for gene therapy in human arthritis and inflammation.
abstract: 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-1beta-induced, NO, PGE(2), 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 PGE(2) by IL-1beta 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-1beta. 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 PGE(2) 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.
authors.affiliation: Laboratory for Functional and Pharmacogenomics, Hospital for Joint Diseases, New York, NY 10003, USA.
authors.forename: Mukundan G
authors.initials: MG
authors.lastname: Attur
authors.forename: Mandar N
authors.initials: MN
authors.lastname: Dave
authors.forename: Mary Y
authors.initials: MY
authors.lastname: Leung
authors.forename: Christine
authors.initials: C
authors.lastname: Cipolletta
authors.forename: Marcia
authors.initials: M
authors.lastname: Meseck
authors.forename: Savio L C
authors.initials: SL
authors.lastname: Woo
authors.forename: Ashok R
authors.initials: AR
authors.lastname: Amin
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000368:Aged; D000818:Animals; D002356:Cartilage / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015316:Genetic Therapy; D005822:Genetic Vectors; D023281:Genomics; D006801:Humans; D007249:Inflammation / Q000628:therapy; D018836:Inflammation Mediators / Q000378:metabolism; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D051379:Mice; D008875:Middle Aged; D009924:Organ Culture Techniques; D010003:Osteoarthritis / Q000378:metabolism* / Q000628:therapy; D011509:Proteoglycans / Q000096:biosynthesis; D011817:Rabbits; D017472:Receptors, Interleukin-1 / Q000235:genetics* / Q000378:metabolism; D053574:Receptors, Interleukin-1 Type II; D013583:Synovial Membrane / Q000187:drug effects / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D018836:Inflammation Mediators; D007375:Interleukin-1; D011509:Proteoglycans; D017472:Receptors, Interleukin-1; D053574:Receptors, Interleukin-1 Type II