Abstract
C17 was first described about ten years ago as a gene expressed in CD34+ cells. A more recent study has suggested a role for C17 in chondrogenesis and development of cartilage. However, based on sequence analysis, we believe that C17 has homology to IL-2 and hence we present the hypothesis that C17 is a cytokine possessing immune-regulatory properties. We provide evidence that C17 is a secreted protein preferentially expressed in chondrocytes, hence in cartilage-rich tissues. Systemic expression of C17 in vivo reduces disease in a collagen antibody-induced arthritis model in mice (CAIA). Joint protection is evident by delayed disease onset, minimal edema, bone protection and absence of diverse histological features of disease. Expression of genes typically associated with acute joint inflammation and erosion of cartilage or bone is blunted in the presence of C17. Consistent with the observed reduction in bone erosion, we demonstrate reduced levels of RANKL in the paws and sera of mice over-expressing C17. Administration of C17 at the peak of disease, however, had no effect on disease progression, indicating that C17's immune-regulatory activity must be most prominent prior to or at the onset of severe joint inflammation. Based on this data we propose C17 as a cytokine that s contributes to immune homeostasis systemically or in a tissue-specific manner in the joint.
Highlights
C17 (Cytl1, C4orf4, Cytokine-like protein 1, Protein C17, UNQ1942/PRO4425) was first mentioned in the literature as a predicted secreted protein, the mRNA of which is expressed in human bone marrow- and cord blood-derived CD34+, but not CD342, cells [1]
Our results suggest that C17 contributes to maintenance of immune homeostasis and support the idea of considering complementation of existing arthritis therapies with C17
The genomic organization of exons and introns in the C17 gene locus, as well as the positioning of exon fusion sites relative to the predicted C17 secondary structure elements, is similar to the arrangement found for genes encoding other IL-2 cytokine family members
Summary
C17 (Cytl, C4orf, Cytokine-like protein 1, Protein C17, UNQ1942/PRO4425) was first mentioned in the literature as a predicted secreted protein, the mRNA of which is expressed in human bone marrow- and cord blood-derived CD34+, but not CD342, cells [1]. C17 reportedly is one of several genes for which elevated mRNA expression was identified in pre-malignant prostate stromal cells [2]. Consistent with the idea of a role for C17 in chondrocyte biology, presence of C17 protein has been reported in human cartilage explants [4]. Based on our hypothesis and the notion of C17’s role in cartilage formation and regeneration, we decided to employ the technology of hydrodynamic delivery [5], in order to test effects of C17 overexpression in the context of acute joint inflammation in vivo. Choice of the CAIA model of rheumatoid arthritis permitted us to focus primarily on the acute inflammatory phase of arthritic disease
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