title: PKC-theta-deficient mice are protected from Th1-dependent antigen-induced arthritis.
abstract: T cell effector functions contribute to the pathogenesis of rheumatoid arthritis. PKC-theta transduces the signal from the TCR through activation of transcription factors NF-kappaB, AP-1, and NFAT. We examined the effects of PKC-theta deficiency on two Th1-dependent models of Ag-induced arthritis and found that PKC-theta-deficient mice develop disease, but at a significantly diminished severity compared with wild-type mice. In the methylated BSA model, cellular infiltrates and articular cartilage damage were mild in the PKC-theta-deficient mice as compared with wild-type mice. Quantitation of histopathology reveals 63 and 77% reduction in overall joint destruction in two independent experiments. In the type II collagen-induced arthritis model, we observed a significant reduction in clinical scores (p < 0.01) in three independent experiments and diminished joint pathology (p < 0.005) in PKC-theta-deficient compared with wild-type littermates. Microcomputerized tomographic imaging revealed that PKC-theta deficiency also protects from bone destruction. PKC-theta-deficient CD4(+) T cells show an impaired proliferative response, decreased intracellular levels of the cytokines IFN-gamma, IL-2, and IL-4, and significantly diminished cell surface expression of the activation markers CD25, CD69, and CD134/OX40 on memory T cells. We demonstrate decreased T-bet expression and significantly reduced IgG1 and IgG2a anti-collagen II Ab levels in PKC-theta-deficient mice. Collectively, our results demonstrate that PKC-theta deficiency results in an attenuated response to Ag-induced arthritis, which is likely mediated by the reduced T cell proliferation, Th1/Th2 cell differentiation and T cell activation before and during disease peak.
authors.affiliation: Inflammation Department, Millennium Pharmaceuticals, Cambridge, MA 02139, USA. ahealy@momentapharma.com
authors.forename: Aileen M
authors.initials: AM
authors.lastname: Healy
authors.forename: Elena
authors.initials: E
authors.lastname: Izmailova
authors.forename: Michael
authors.initials: M
authors.lastname: Fitzgerald
authors.forename: Russell
authors.initials: R
authors.lastname: Walker
authors.forename: Maureen
authors.initials: M
authors.lastname: Hattersley
authors.forename: Matthew
authors.initials: M
authors.lastname: Silva
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Siebert
authors.forename: Jennifer
authors.initials: J
authors.lastname: Terkelsen
authors.forename: Dominic
authors.initials: D
authors.lastname: Picarella
authors.forename: Michael D
authors.initials: MD
authors.lastname: Pickard
authors.forename: Brett
authors.initials: B
authors.lastname: LeClair
authors.forename: Sudeep
authors.initials: S
authors.lastname: Chandra
authors.forename: Bruce
authors.initials: B
authors.lastname: Jaffee
mesh_terms: D000818:Animals; D000941:Antigens / Q000008:administration & dosage* / Q000276:immunology; D001169:Arthritis, Experimental / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation; D003094:Collagen / Q000008:administration & dosage / Q000276:immunology; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D005260:Female; D016130:Immunophenotyping; D007527:Isoenzymes / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D000074121:Protein Kinase C-theta; D012710:Serum Albumin, Bovine / Q000008:administration & dosage* / Q000276:immunology; D020825:T-Box Domain Proteins; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology; D014157:Transcription Factors / Q000096:biosynthesis; D015854:Up-Regulation / Q000276:immunology; D000098815:T-bet Transcription Factor
chemical_list: D000941:Antigens; D001323:Autoantibodies; D007527:Isoenzymes; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; C029180:methylated bovine serum albumin; D012710:Serum Albumin, Bovine; D003094:Collagen; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta