Objective: Transforming growth factor-ß (TGF-ß) plays a critical role in the initiation and resolution of autoimmune diseases and chronic inflammation. The aim of the current study was to characterize the molecular role of TGF-ß signaling in salivary gland inflammation. Methods: We impaired TGF-ß signaling in mouse salivary glands by conditionally disrupting expression of TGF-ß receptor I using two different strategies: 1. by generating conditional knockout (TßRICOKO) mice by crossing TGF-ß receptor I floxed mice with the mouse mammary tumor virus-Cre mice, and 2. by delivering adenoviral vector containing Cre to mouse salivary glands of TGF-ß receptor I floxed mice via retrograde infusion of the cannulated main excretory ducts of submandibular glands. Results: TßRICOKO mice were born normal; however, only female TßRICOKO mice developed severe multifocal inflammation in salivary glands, mammary glands, and the heart. The inflammatory disorder affected normal growth and resulted in death as early as 4 weeks of age. Interestingly, male TßRICOKO mice did not exhibit any signs of inflammation. The female TßRICOKO mice also displayed an increase in Th1 proinflammatory cytokines in salivary glands and exhibited an upregulation of peripheral T cells. In addition, these mice also showed an atypical distribution of aquaporin-5 in their salivary glands, likely indicating secretory impairment. Administration of an adenoviral vector encoding Cre recombinase to the salivary glands resulted in inflammatory foci only in the salivary glands of female TßRICOKO floxed mice, but not in wild-type male and female mice or male TßRI floxed mice. Conclusion: These results indicate that female mice are more susceptible to developing inflammatory disorders because of impaired TGF-ß signaling.

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