title: Interleukin-6 inhibits apoptosis of exocrine gland tissues under inflammatory conditions.
abstract: Interleukin (IL)-6 is a multi-functional cytokine that can either promote or suppress tissue inflammation depending on the specific disease context. IL-6 is elevated in the exocrine glands and serum of patients with Sjögren's syndrome (SS), but the specific role of IL-6 in the pathogenesis of this disease has not been defined. In this study, we showed that IL-6 expression levels were increased with age in C56BL/6.NOD-Aec1Aec2 mice, a primary SS model, and higher than the control C57BL/6 mice. To assess the role of IL-6 during the immunological phase of SS development, a neutralizing anti-IL-6 antibody was administered into 16 week-old female C56BL/6.NOD-Aec1Aec2 mice, 3 times weekly for a consecutive 8 weeks. Neutralization of endogenous IL-6 throughout the immunological phase of SS development led to increased apoptosis, caspase-3 activation, leukocytic infiltration, and IFN-γ- and TNF-α production in the salivary gland. To further determine the effect of IL-6 on the apoptosis of exocrine gland cells, recombinant human IL-6 or the neutralizing anti-IL-6 antibody was injected into female C57BL/6 mice that received concurrent injection of anti-CD3 antibody to induce the apoptosis of exocrine gland tissues. Neutralization of IL-6 enhanced, whereas administration of IL-6 inhibited apoptosis and caspase-3 activation in salivary and lacrimal glands in this model. The apoptosis-suppressing effect of IL-6 was associated with up-regulation of Bcl-xL and Mcl-1 in both glands. Moreover, IL-6 treatment induced activation of STAT3 and up-regulated Bcl-xL and Mcl-1 gene expression in a human salivary gland epithelial cell line. In conclusion, IL-6 inhibits the apoptosis of exocrine gland tissues and exerts a tissue-protective effect under inflammatory conditions including SS. These findings suggest the possibility of using this property of IL-6 to preserve exocrine gland tissue integrity and function under autoimmune and inflammatory conditions.
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA; Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA. Electronic address: jzhou@forsyth.org.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA. Electronic address: junojin1@gmail.com.
authors.forename: Jun-O
authors.initials: JO
authors.lastname: Jin
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA; Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA. Electronic address: ektaspatel01@gmail.com.
authors.forename: Ekta S
authors.initials: ES
authors.lastname: Patel
authors.affiliation: Department of Immunology and Infectious Diseases, The Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA; Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA. Electronic address: qyu@forsyth.org.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005088:Exocrine Glands / Q000276:immunology*; D005260:Female; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000235:genetics; D015850:Interleukin-6 / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D011994:Recombinant Proteins / Q000008:administration & dosage; D050796:STAT3 Transcription Factor / Q000235:genetics; D012469:Salivary Glands / Q000276:immunology* / Q000503:physiopathology* / Q000648:ultrastructure; D012859:Sjogren's Syndrome / Q000276:immunology* / Q000503:physiopathology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D051020:bcl-X Protein / Q000235:genetics
chemical_list: D057134:Antibodies, Neutralizing; D015850:Interleukin-6; D011994:Recombinant Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D051020:bcl-X Protein; C577686:interleukin-6, mouse; D007371:Interferon-gamma; D053148:Caspase 3
keywords: Apoptosis; Exocrine gland; Inflammation; Interleukin-6; Sjögren’s syndrome