| 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
(Affiliation: Inflammation Department, Millennium Pharmaceuticals, Cambridge, MA 02139, USA. ahealy at momentapharma.com)
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| Journal | Journal of immunology (Baltimore, Md. : 1950)
(J Immunol)
Vol. 177
Issue 3
Pg. 1886-93
(Aug 1 2006)
ISSN: 0022-1767 United States |
| PMID | 16849501
(Publication Type: Journal Article)
|
| Chemical References |
- Antigens
- Autoantibodies
- Isoenzymes
- Serum Albumin, Bovine
- T-Box Domain Proteins
- T-box transcription factor TBX21
- Transcription Factors
- methylated bovine serum albumin
- Collagen
- Prkcq protein, mouse
- Protein Kinase C
|
| 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)
- Serum Albumin, Bovine
(administration & dosage, immunology)
- T-Box Domain Proteins
- T-Lymphocytes
(immunology, pathology)
- Th1 Cells
(immunology, pathology)
- Transcription Factors
(biosynthesis)
- Up-Regulation
(immunology)
|
