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: Aileen M Healy, Elena Izmailova, Michael Fitzgerald, Russell Walker, Maureen Hattersley, Matthew Silva, Elizabeth Siebert, Jennifer Terkelsen, Dominic Picarella, Michael D Pickard, Brett LeClair, Sudeep Chandra, Bruce Jaffee
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 177 Issue 3 Pg. 1886-93 (Aug 01 2006) ISSN: 0022-1767 [Print] United States
• PMID: 16849501 (Publication Type: Journal Article)

Chemical References

• Antigens
• Autoantibodies
• Isoenzymes
• T-Box Domain Proteins
• T-box transcription factor TBX21
• Transcription Factors
• methylated bovine serum albumin
• Serum Albumin, Bovine
• Collagen
• Prkcq protein, mouse
• Protein Kinase C
• Protein Kinase C-theta

Topics

• Animals
• Antigens (administration & dosage, immunology)
• Arthritis, Experimental (enzymology, genetics, immunology, prevention & control)
• Autoantibodies (biosynthesis, blood)
• Cell Movement (genetics, immunology)
• Cell Proliferation
• Collagen (administration & dosage, immunology)
• Down-Regulation (genetics, immunology)
• Female
• Immunophenotyping
• Isoenzymes (deficiency, genetics, physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred DBA
• Mice, Knockout
• Protein Kinase C (deficiency, genetics, physiology)
• Protein Kinase C-theta
• Serum Albumin, Bovine (administration & dosage, immunology)
• T-Box Domain Proteins
• T-Lymphocytes (immunology, pathology)
• Th1 Cells (immunology, pathology)
• Transcription Factors (biosynthesis)
• Up-Regulation (immunology)