PKC-theta-deficient mice are protected from Th1-dependent antigen-induced arthritis.
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.
Healy
Aileen M
AM
Inflammation Department, Millennium Pharmaceuticals, Cambridge, MA 02139, USA. ahealy@momentapharma.com
Izmailova
Elena
E
Fitzgerald
Michael
M
Walker
Russell
R
Hattersley
Maureen
M
Silva
Matthew
M
Siebert
Elizabeth
E
Terkelsen
Jennifer
J
Picarella
Dominic
D
Pickard
Michael D
MD
LeClair
Brett
B
Chandra
Sudeep
S
Jaffee
Bruce
B
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
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