Background/Purpose: Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disorder mainly affecting the exocrine glands. However, it is now clear that both immune and non-immune mechanisms are responsible salivary gland dysfunction in this disorder. Thus, drugs capable of inducing immunosuppression as well as directly influencing salivary gland function would be highly desirable as therapeutics for SS. Adenosine is a major anti-inflammatory metabolite generated during tissue injury and it signals through four distinct G protein-coupled receptors, termed A1AR, A2aAR, A2bAR and A3AR. In addition it can have direct effects on different aspects of cellular metabolism. Thus, in this study we have tested the efficacy of adenosine A2b receptor agonist Bay60-6583 for restoration of salivary gland function in a mouse model for SS-like disorder.

Methods: The B6.Aec1Aec2 mouse model for SS-like disorder was used for this study. Gene expression of adenosine receptors on human and mouse submandibular gland cell lines, as well as mouse salivary glands was determined by real time PCR. ERK phosphorylation in cell lines treated with the drug and presence of serum autoantibodies were analyzed by western blotting. Mice with established glandular dysfunction were treated with the drug, 8 times, every third day by intraperitoneal route. Saliva production was measured following pilocarpine injection. Cytokine levels in sera were measured using Bioplex assay system. Formalin fixed salivary gland sections were stained with H and E and presence of inflammatory cell infiltrates quantified by Stereology.

Results: All adenosine receptors were expressed in the mouse salivary glands and in the mouse and human cell lines. Bay60-6583 readily induced ERK phosphorylation in the human and mouse cell lines. Mice treated with Bay60-6583 showed significant improvement in their saliva production than control (vehicle treated) mice. Salivary glands from drug treated mice showed significantly lower inflammatory cell infiltrates. Surprisingly, the inflammatory cytokine and autoantibody levels between the vehicle and drug treated mice were not different.

Conclusion: Our study has established for the first time the presence of functional adenosine receptors on salivary gland cells. The restoration of glandular function in drug treated mice demonstrates the potential of targeting adenosine receptors for therapeutic intervention in SS.  Our study also demonstrates that in this mouse model, circulating inflammatory cytokine and autoantibody levels were dissociated from glandular dysfunction. This finding suggests that in some SS patients, biomarkers other than circulating cytokines and autoantibodies might  be more relevant for following disease progression.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/adenosine-a2b-receptor-agonist-bay60-6583-restores-salivary-gland-function-in-a-mouse-model-for-sjogrens-syndrome/