title: Female mice are more susceptible to developing inflammatory disorders due to impaired transforming growth factor beta signaling in salivary glands.
abstract: OBJECTIVE
  Transforming growth factor beta (TGFbeta) plays a key role in the onset and resolution of autoimmune diseases and chronic inflammation. The aim of this study was to delineate the precise function of TGFbeta signaling in salivary gland inflammation.
  
  
  METHODS
  We impaired TGFbeta signaling in mouse salivary glands by conditionally inactivating expression of TGFbeta receptor type I (TGFbetaRI), either by using mouse mammary tumor virus-Cre mice or by delivering adenoviral vector containing Cre to mouse salivary glands via retrograde infusion of the cannulated main excretory ducts of submandibular glands.
  
  
  RESULTS
  TGFbetaRI-conditional knockout (TGFbetaRI-coko) mice were born normal; however, female TGFbetaRI-coko mice developed severe multifocal inflammation in salivary and mammary glands and in the heart. The inflammatory disorder affected normal growth and resulted in the death of the mice at ages 4-5 weeks. Interestingly, male TGFbetaRI-coko mice did not exhibit any signs of inflammation. The female TGFbetaRI-coko mice also showed an increase in Th1 proinflammatory cytokines in salivary glands and exhibited an up-regulation of peripheral T cells. In addition, these mice showed an atypical distribution of aquaporin 5 in their salivary glands, suggesting likely secretory impairment. Administration of an adenoviral vector encoding Cre recombinase into the salivary glands resulted in inflammatory foci only in the glands of female TGFbetaRI-loxP-flanked (floxed) mice (TGFbetaRI-f/f mice), but not in those of male and female wild-type mice or male TGFbetaRI-f/f mice.
  
  
  CONCLUSIONS
  These results suggest that female mice are uniquely more susceptible to developing inflammatory disorders due to impaired TGFbeta signaling in their salivary glands.
authors.affiliation: National Institute of Dental and Craniofacial Research, NIH, Bethesda, Maryland 20892, USA.
authors.forename: Seshagiri R
authors.initials: SR
authors.lastname: Nandula
authors.forename: Shoba
authors.initials: S
authors.lastname: Amarnath
authors.forename: Alfredo
authors.initials: A
authors.lastname: Molinolo
authors.forename: Bidhan C
authors.initials: BC
authors.lastname: Bandyopadhyay
authors.forename: Bradford
authors.initials: B
authors.lastname: Hall
authors.forename: Corinne M
authors.initials: CM
authors.lastname: Goldsmith
authors.forename: Changyu
authors.initials: C
authors.lastname: Zheng
authors.forename: Jonas
authors.initials: J
authors.lastname: Larsson
authors.forename: Taduru
authors.initials: T
authors.lastname: Sreenath
authors.forename: WanJun
authors.initials: W
authors.lastname: Chen
authors.forename: Indu S
authors.initials: IS
authors.lastname: Ambudkar
authors.forename: Stefan
authors.initials: S
authors.lastname: Karlsson
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Baum
authors.forename: Ashok B
authors.initials: AB
authors.lastname: Kulkarni
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000502:physiology; D000818:Animals; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000503:physiopathology*; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology; D012469:Salivary Glands / Q000473:pathology / Q000503:physiopathology*; D012727:Sex Characteristics; D015398:Signal Transduction / Q000502:physiology*; D012859:Sjogren's Syndrome / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I