title: Activation of innate immune responses through Toll-like receptor 3 causes a rapid loss of salivary gland function.
abstract: BACKGROUND
  Recent studies have demonstrated the expression of Toll-like receptor 3 (TLR3) in salivary glands and epithelial cell lines derived from Sjögren's syndrome (SS) patients. As viral infections are considered to be a trigger for SS, in this study we investigated whether in vivo engagement of TLR3 affects salivary gland function.
  
  
  METHODS
  Female New Zealand Black/WF1 mice were repeatedly injected with polyinosinic:polycytidylic acid [poly(I:C)]. TLR3 expression within submandibular glands was studied using immunohistochemistry. RNA levels of inflammatory cytokines in the submandibular glands were determined by real time polymerase chain reaction. Pilocarpine induced saliva volume was used as an index of glandular function.
  
  
  RESULTS
  Immunohistochemical analysis of submandibular glands showed TLR3 expression in epithelium of serous and mucous acini, granular convoluted tubules, and ducts. Poly(I:C) treatment rapidly up-regulated the mRNA levels of type I interferon (IFN) and inflammatory cytokines in the submandibular glands. One week after treatment, the saliva volumes in poly(I:C) treated mice were significantly reduced in comparison with the phosphate-buffered saline (PBS) treated mice. Hematoxylin and eosin staining showed that salivary gland histology was normal and lymphocytic foci were not detected. Glandular function recovered after poly(I:C) treatment was stopped.
  
  
  CONCLUSIONS
  Our results demonstrate that engagement of TLR3 within the salivary glands results in a rapid loss of glandular function. This phenomenon is associated with the production of type I IFN and inflammatory cytokines in the salivary glands. Restoration of glandular function suggests that for viral etiology of SS, a chronic infection of salivary glands might be necessary.
authors.affiliation: Division of Rheumatology, Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA 22908, USA. usd7w@virginia.edu
authors.forename: Umesh S
authors.initials: US
authors.lastname: Deshmukh
authors.forename: Seshagiri Rao
authors.initials: SR
authors.lastname: Nandula
authors.forename: Pushpa-Rekha
authors.initials: PR
authors.lastname: Thimmalapura
authors.forename: Yogesh M
authors.initials: YM
authors.lastname: Scindia
authors.forename: Harini
authors.initials: H
authors.lastname: Bagavant
mesh_terms: D000818:Animals; D018946:Chemokine CCL5 / Q000187:drug effects / Q000276:immunology; D005260:Female; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology*; D007150:Immunohistochemistry; D007369:Interferon Inducers / Q000494:pharmacology; D007370:Interferon Type I / Q000187:drug effects / Q000276:immunology; D053583:Interleukin-1beta / Q000187:drug effects / Q000276:immunology; D015850:Interleukin-6 / Q000032:analysis / Q000276:immunology; D051379:Mice; D008814:Mice, Inbred NZB; D018721:Muscarinic Agonists / Q000494:pharmacology; D010862:Pilocarpine / Q000494:pharmacology; D011070:Poly I-C / Q000494:pharmacology; D016133:Polymerase Chain Reaction / Q000379:methods; D012463:Saliva / Q000187:drug effects / Q000378:metabolism; D018987:Salivary Ducts / Q000187:drug effects / Q000276:immunology; D012636:Secretory Rate / Q000187:drug effects; D013363:Submandibular Gland / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology*; D051196:Toll-Like Receptor 3 / Q000187:drug effects / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation
chemical_list: C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D007369:Interferon Inducers; D007370:Interferon Type I; D053583:Interleukin-1beta; D015850:Interleukin-6; D018721:Muscarinic Agonists; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; D014409:Tumor Necrosis Factor-alpha; D010862:Pilocarpine; D011070:Poly I-C