title: Innate Stat3-mediated induction of the antimicrobial protein Reg3γ is required for host defense against MRSA pneumonia.
abstract: Pulmonary Staphylococcus aureus (SA) infections are a public health concern and a major complication of hyper-IgE syndrome, caused by mutations in STAT3. In contrast to previous findings of skin infection, we observed that clearance of SA from the lung did not require T, B, or NK cells but did require Stat3 activation. Immunohistochemistry showed robust Stat3 phosphorylation in the lung epithelium. We identified that a critical Stat3 target gene in lung epithelium is Reg3g (regenerating islet-derived 3 γ), a gene which is highly expressed in gastrointestinal epithelium but whose role in pulmonary host defense is uncharacterized. Stat3 regulated Reg3g transcription through direct binding at the Reg3g promoter region. Recombinant Reg3γ bound to SA and had both bacteriostatic and bactericidal activity in a dose-dependent fashion. Stat3 inhibition in vivo reduced Reg3g transcripts in the lung, and more importantly, recombinant Reg3γ rescued mice from defective SA clearance. These findings reveal an antibacterial function for lung epithelium through Stat3-mediated induction of Reg3γ.
authors: Department of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors: Sun-Mi
authors: SM
authors: Choi
authors: Jeremy P
authors: JP
authors: McAleer
authors: Mingquan
authors: M
authors: Zheng
authors: Derek A
authors: DA
authors: Pociask
authors: Mark H
authors: MH
authors: Kaplan
authors: Shulin
authors: S
authors: Qin
authors: Todd A
authors: TA
authors: Reinhart
authors: Jay K
authors: JK
authors: Kolls
mesh_terms: D000818:Animals; D050822:Cytokine Receptor gp130 / Q000502:physiology; D007113:Immunity, Innate; D015850:Interleukin-6 / Q000096:biosynthesis; D053605:Leukemia Inhibitory Factor / Q000096:biosynthesis; D008168:Lung / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000073718:Pancreatitis-Associated Proteins; D011023:Pneumonia, Staphylococcal / Q000276:immunology*; D011506:Proteins / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000502:physiology*
chemical_list: C494200:Il6st protein, mouse; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D000073718:Pancreatitis-Associated Proteins; D011506:Proteins; C490255:Reg3g protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D050822:Cytokine Receptor gp130
references: Bone Marrow Transplant. 2000 Jun;25(12):1303-5
references: 10871737
references: Eur Respir J. 2009 Dec;34(6):1470-6
references: 19948913
references: Eur Respir J. 2004 Feb;23(2):327-33
references: 14979512
references: J Infect Dis. 2006 Jan 15;193(2):172-9
references: 16362880
references: J Immunol. 2011 Feb 1;186(3):1666-1674
references: 21178015
references: Chest. 2009 Nov;136(5):1407-1412
references: 19892681
references: Protein Expr Purif. 2006 Jul;48(1):151-9
references: 16504538
references: Clin Microbiol Rev. 2010 Jul;23(3):616-87
references: 20610826
references: Ann Intern Med. 2006 Mar 7;144(5):318-25
references: 16520472
references: JAMA. 2007 Oct 17;298(15):1763-71
references: 17940231
references: Clin Rev Allergy Immunol. 2010 Feb;38(1):32-8
references: 19452285
references: Am J Pathol. 2008 Dec;173(6):1657-68
references: 18974303
references: J Biol Chem. 2009 Feb 20;284(8):4881-8
references: 19095652
references: J Immunol. 2008 Apr 15;180(8):5558-68
references: 18390740
references: J Immunol. 2006 Jul 1;177(1):527-37
references: 16785550
references: Nat Med. 2008 Mar;14(3):282-9
references: 18264109
references: J Clin Invest. 2010 May;120(5):1762-73
references: 20364087
references: BMC Genomics. 2007 Dec 10;8:455
references: 18070348
references: Blood. 2002 May 1;99(9):3119-28
references: 11964273
references: Pediatrics. 2011 Dec;128(6):e1450-8
references: 22065262
references: J Exp Med. 2009 Jul 6;206(7):1465-72
references: 19564350
references: Lancet. 2010 May 1;375(9725):1557-68
references: 20206987
references: Science. 2011 Oct 14;334(6053):255-8
references: 21998396
references: J Exp Med. 2009 Jun 8;206(6):1291-301
references: 19487419
references: J Immunol. 2004 Mar 15;172(6):3377-81
references: 15004134
references: Am J Respir Cell Mol Biol. 2008 Jun;38(6):699-706
references: 18192501
references: Semin Immunopathol. 2012 Mar;34(2):281-97
references: 22037948
references: Nat Rev Cancer. 2009 Nov;9(11):798-809
references: 19851315
references: J Allergy Clin Immunol. 2010 Aug;126(2):392-4
references: 20584545
references: J Allergy Clin Immunol. 2005 Aug;116(2):305-11
references: 16083784
references: J Immunol. 2007 Nov 15;179(10):6933-42
references: 17982084