title: Interleukin-17 Impairs Salivary Tight Junction Integrity in Sjögren's Syndrome.
abstract: Sjögren's syndrome (SS) is an inflammatory autoimmune disease that causes secretory dysfunction of the salivary glands. It has been reported that proinflammatory cytokine interleukin-17 (IL-17) was elevated and tight junction (TJ) integrity disrupted in minor salivary glands from SS patients. However, whether the elevated IL-17 in SS affects TJ integrity and thereby alters the function of salivary gland is unknown. Here, by using nonobese diabetic (NOD) mice as SS model, we found that the stimulated salivary flow rate was significantly decreased in NOD mice. Lymphocyte infiltration was mainly observed in submandibular glands (SMGs), but not parotid glands (PGs), of NOD mice. IL-17 was significantly increased and mainly located in lymphocytic-infiltrating regions in SMGs but not detectable in PGs of NOD mice. Meanwhile, the epithelial barrier function was disrupted, as evidenced by an increased paracellular tracer clearance and an enlarged acinar TJ width in SMGs of NOD mice. Furthermore, claudin-1 and -3 were elevated especially at the basolateral membranes, whereas claudin-4, occludin, and zonula occludens-1 (ZO-1) were reduced in SMGs of NOD mice. Moreover, occludin and ZO-1 were dispersed into cytoplasm in SMGs of NOD mice. However, no change in the expression and distribution of TJ proteins was found in PGs. In vitro, IL-17 significantly decreased the levels and apical staining of claudin-4 and ZO-1 proteins in the cultured SMG tissues, as well as claudin-1, occludin, and ZO-1 in PG tissues. Moreover, IL-17 activated the phosphorylation of IκBα and p65 in SMG cells, whereas pretreatment with NF-κB inhibitor pyrrolidine dithiocarbamate suppressed the IL-17-induced downregulation of claudin-4 and ZO-1 in SMG tissues. Taken together, these findings indicate that IL-17 derived from infiltrating lymphocyte impairs the integrity of TJ barrier through NF-κB signaling pathway, and thus might contribute to salivary gland dysfunction in SS.
authors.affiliation: Department of Oral Medicine and Center for Salivary Gland Diseases of Peking University School and Hospital of Stomatology, Beijing, P.R. China.
authors.forename: L W
authors.initials: LW
authors.lastname: Zhang
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, P.R. China.
authors.forename: X
authors.initials: X
authors.lastname: Cong
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, P.R. China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, P.R. China.
authors.forename: T
authors.initials: T
authors.lastname: Wei
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, P.R. China.
authors.forename: Y C
authors.initials: YC
authors.lastname: Su
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, P.R. China Department of Dentistry, Santa Cecília University, Santos, Brazil.
authors.forename: A C A
authors.initials: AC
authors.lastname: Serrão
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, P.R. China Department of Dentistry, Santa Cecília University, Santos, Brazil.
authors.forename: A R T
authors.initials: AR
authors.lastname: Brito
authors.affiliation: Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, P.R. China.
authors.forename: G Y
authors.initials: GY
authors.lastname: Yu
authors.affiliation: Department of Oral Medicine and Center for Salivary Gland Diseases of Peking University School and Hospital of Stomatology, Beijing, P.R. China honghua1968@aliyun.com.
authors.forename: H
authors.initials: H
authors.lastname: Hua
authors.affiliation: Department of Physiology and Pathophysiology, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, P.R. China honghua1968@aliyun.com.
authors.forename: L L
authors.initials: LL
authors.lastname: Wu
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005455:Fluorescent Antibody Technique; D020381:Interleukin-17 / Q000502:physiology*; D008214:Lymphocytes / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D046529:Microscopy, Electron, Transmission; D010306:Parotid Gland / Q000503:physiopathology; D012463:Saliva / Q000378:metabolism; D012469:Salivary Glands / Q000503:physiopathology*; D012859:Sjogren's Syndrome / Q000503:physiopathology*; D013363:Submandibular Gland / Q000503:physiopathology; D019108:Tight Junctions / Q000502:physiology*
chemical_list: D020381:Interleukin-17
keywords: claudins; nonobese diabetic mice; occludin; parotid gland; submandibular gland; zonula occludens-1