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X. Li, K. Wu, M. MacVeigh, S. F. Hamm-Alvarez; Increased Expression of Cathepsins and Their Regulatory Cytokines in the Lacrimal Gland of Male NOD Mouse. Invest. Ophthalmol. Vis. Sci. 2008;49(13):425.
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© ARVO (1962-2015); The Authors (2016-present)
Lymphocytic infiltration and destruction of the lacrimal gland (LG) are characteristics of Sjögren's Syndrome (SjS). The male NOD mouse is an established model for the autoimmune dacryoadenitis characteristic of SjS. Lymphocytic infiltration occurs in response to neoautoantigen presentation while degradation of extracellular matrix by proteases facilitates this infiltration. The purpose of this study was to identify and characterize the candidate genes and their products involved in these pathogenic processes in the male NOD mouse model.
cDNA microarray was conducted for evalution of gene expression profiles. The differentially expressed genes of interest were validated by real-time PCR. The corresponding proteins were localized by immunofluorescence microscopy (IF). Total RNA pools for the experiments were purified from LGs of male NOD, NOD SCID and BALB/c mice at 12 weeks of age. Cryonic sections of LGs for IF were prepared from mice of same source.
The cDNA micrarray revealed increased mRNA levels of Cathepsin S (CtsS), H (CtsH), TNF-α and IFN-γ in male NOD LGs compared to the matched BALB/c control. The fold changes were 5.7, 2.4, 4.5 and 14.5 respectively. The results were validated by real-time PCR with RNAs from the LGs of NOD and BALB/c mice, and were in parallel tested with RNAs from the LGs of NOD SCID mice of both genders. The mRNA levels of CtsS and CtsH in NOD LGs were 8.8-fold and 11.0-fold respectively as high as in the BALB/c control. The mRNA levels in NOD SCID mice were 6.3-fold and 3.0-fold as high as in the BALB/c control. The mRNA levels of TNF-α and IFN-γ in male NOD LGs were 18.4-fold and 10.1-fold respectively over the BALB/c control. The mRNA level of TNF-α in NOD SCID mice was 7.0-fold increase whereas that of IFN-γ was 70% of the BALB/c control. IF identified CtsS and CtsH proteins in the LG of NOD but not BALB/c LG; CtsS was localized to large vesicles comparable to secretory vesicles and/or lysosomes and CtsH to the cytoplasm of infiltrating inflammatory cells.
CtsS and CtsH are induced in dacryoadenitis in the LG of NOD mouse concomitantly with their potential regulatory cytokines TNF-α and IFN-γ. TNF-α is upregulated in both LG and infiltrated inflammatory cells, whereas IFN-γ upregulation appears only in the latter. The results altogether with previous studies published by others groups suggest that CtsS and CtsH are upregulated in the acinar cells and the infiltrated inflammatory cells respectively by TNF-α and/or IFN-γ.
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