title: IL-17A and IFN-γ synergistically induce RNase 7 expression via STAT3 in primary keratinocytes.
abstract: Human keratinocytes produce several antimicrobial peptides and proteins (AMP) which contribute to the protection of human skin against infection. RNase 7 is a major AMP involved in cutaneous defense with a high expression in keratinocytes and a broad spectrum of antimicrobial activity. The cytokine IL-17A has been recently identified as a potent inducer of several AMP in keratinocytes. Since the role of IL-17A to induce RNase 7 expression is unknown we analyzed IL-17A alone and in combination with other cytokines to induce RNase 7 expression in keratinocytes. Whereas IL-17A alone only weakly induced RNase 7 expression, the synergistic combination of IL-17A and IFN-γ (IL-17A/IFN-γ) was identified as a potent inducer of RNase 7 expression. This combination was more effective in inducing RNase 7 than the combination of IL-17A/TNF-α, a combination previously identified as a strong inducer of psoriasis-related immune response genes including several AMP. IFN-γ and IL-17A both have been reported to activate the transcription factor STAT3 (Signal transducer and activator of transcription 3). Therefore we investigated the influence of STAT3 on the IL-17A/IFN-γ -mediated RNase 7 induction. The use of a STAT3 inhibitor as well as siRNA-mediated downregulation of STAT3 resulted in a diminished IL-17A/IFN-γ -mediated RNase 7 induction in keratinocytes indicating that STAT3 is involved in this process. Similarly as seen with RNase 7, treatment of keratinocytes with IL-17A/IFN-γ revealed also a synergistic induction of gene expression of the AMP human beta-defensin (hBD)-2 and -3 as well as the S100 protein psoriasin (S100A7) indicating that the combination of IL-17A/IFN-γ is a potent inducer of various AMP classes in general. This was also reflected by an increase of the Staphylococcus aureus-killing activity of IL-17A/IFN-γ -treated keratinocytes.
authors.affiliation: Department of Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany.
authors.forename: Maren
authors.initials: M
authors.lastname: Simanski
authors.forename: Franziska
authors.initials: F
authors.lastname: Rademacher
authors.forename: Lena
authors.initials: L
authors.lastname: Schröder
authors.forename: Hanna Maria
authors.initials: HM
authors.lastname: Schumacher
authors.forename: Regine
authors.initials: R
authors.lastname: Gläser
authors.forename: Jürgen
authors.initials: J
authors.lastname: Harder
mesh_terms: D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D020381:Interleukin-17 / Q000494:pharmacology*; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism* / Q000382:microbiology; D012260:Ribonucleases / Q000235:genetics / Q000378:metabolism*; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000502:physiology; D023083:beta-Defensins / Q000235:genetics
chemical_list: C422950:DEFB103A protein, human; C106641:DEFB4A protein, human; D020381:Interleukin-17; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; C089242:S100A7 protein, human; D050796:STAT3 Transcription Factor; D023083:beta-Defensins; D007371:Interferon-gamma; D012260:Ribonucleases; C470000:Ribonuclease 7
references.citation: Immunology. 2010 Mar;129(3):311-21
references.pmid: 20409152
references.citation: Nat Med. 2006 Jun;12(6):636-41
references.pmid: 16751768
references.citation: J Immunol. 2010 Mar 24;184(9):5263-5270
references.pmid: 20335534
references.citation: J Leukoc Biol. 2005 Apr;77(4):476-86
references.pmid: 15629886
references.citation: J Invest Dermatol. 2005 Dec;125(6):1163-73
references.pmid: 16354186
references.citation: J Biol Chem. 2002 Nov 29;277(48):46779-84
references.pmid: 12244054
references.citation: PLoS One. 2009 Jul 29;4(7):e6424
references.pmid: 19641608
references.citation: Eur J Biochem. 1996 Jun 1;238(2):325-32
references.pmid: 8681941
references.citation: Nat Genet. 2008 Jan;40(1):23-5
references.pmid: 18059266
references.citation: J Immunol. 2008 Oct 1;181(7):4733-41
references.pmid: 18802076
references.citation: J Immunol. 2008 Nov 15;181(10):7420-7
references.pmid: 18981165
references.citation: Nat Immunol. 2011 Oct 12;12(12):1151-8
references.pmid: 21993849
references.citation: J Biol Chem. 1999 Mar 26;274(13):8405-10
references.pmid: 10085071
references.citation: Trends Immunol. 2009 Mar;30(3):131-41
references.pmid: 19217824
references.citation: J Invest Dermatol. 2011 Dec;131(12):2401-8
references.pmid: 21796151
references.citation: Cell Mol Life Sci. 1999 Oct 1;56(1-2):32-46
references.pmid: 11213259
references.citation: Allergol Int. 2012 Jun;61(2):191-6
references.pmid: 22441639
references.citation: J Invest Dermatol. 2010 Dec;130(12):2836-8
references.pmid: 20668470
references.citation: J Clin Invest. 2010 May;120(5):1762-73
references.pmid: 20364087
references.citation: J Immunol. 2004 Sep 1;173(5):3482-91
references.pmid: 15322213
references.citation: Nature. 2003 Apr 3;422(6931):522-6
references.pmid: 12660734
references.citation: J Invest Dermatol. 2011 Mar;131(3):677-87
references.pmid: 21085185
references.citation: Scand J Infect Dis. 2003;35(9):670-6
references.pmid: 14620153
references.citation: Nature. 1997 Jun 26;387(6636):861
references.pmid: 9202117
references.citation: J Exp Med. 2009 Jun 8;206(6):1291-301
references.pmid: 19487419
references.citation: J Allergy Clin Immunol. 2008 Aug;122(2):261-6
references.pmid: 18439663
references.citation: Cell Mol Life Sci. 2006 Jun;63(11):1294-313
references.pmid: 16710608
references.citation: J Am Acad Dermatol. 1995 Jun;32(6):982-6
references.pmid: 7751469
references.citation: Science. 1999 Oct 1;286(5437):113-7
references.pmid: 10506557
references.citation: J Immunol. 2002 Jul 1;169(1):434-42
references.pmid: 12077274
references.citation: Nat Immunol. 2005 Jun;6(6):551-7
references.pmid: 15908936
references.citation: J Infect Dis. 2009 Dec 15;200(12):1907-15
references.pmid: 19919305
references.citation: J Exp Med. 2006 Oct 2;203(10):2271-9
references.pmid: 16982811
references.citation: J Invest Dermatol. 2010 May;130(5):1355-64
references.pmid: 20107483
references.citation: J Allergy Clin Immunol. 2009 Jan;123(1):59-66.e4
references.pmid: 19056110
references.citation: J Endotoxin Res. 2007;13(6):317-38
references.pmid: 18182460
references.citation: Nat Immunol. 2005 Jan;6(1):57-64
references.pmid: 15568027
references.citation: J Biol Chem. 2001 Feb 23;276(8):5707-13
references.pmid: 11085990
references.citation: Nat Immunol. 2001 Dec;2(12):1133-7
references.pmid: 11694882
references.citation: Nat Immunol. 2011 Oct 12;12(12):1159-66
references.pmid: 21993848
references.citation: Nature. 2001 Nov 22;414(6862):454-7
references.pmid: 11719807