title: Bovine lactoferricin-induced anti-inflammation is, in part, via up-regulation of interleukin-11 by secondary activation of STAT3 in human articular cartilage.
abstract: Bovine lactoferricin (LfcinB), a multifunctional peptide, was recently demonstrated to be anti-catabolic and anti-inflammatory in human articular cartilage. LfcinB blocks IL-1-mediated proteoglycan depletion, matrix-degrading enzyme expression, and pro-inflammatory mediator induction. LfcinB selectively activates ERK1/2, p38 (but not JNK), and Akt signaling. However, the relationship between these pathways and LfcinB target genes has never been explored. In this study, we uncovered the remarkable ability of LfcinB in the induction of an anti-inflammatory cytokine, IL-11. LfcinB binds to cell surface heparan sulfate to initiate ERK1/2 signaling and activate AP-1 complexes composed of c-Fos and JunD, which transactivate the IL-11 gene. The induced IL-11 functions as an anti-inflammatory and chondroprotective cytokine in articular chondrocytes. Our data show that IL-11 directly attenuates IL-1-mediated catabolic and inflammatory processes ex vivo and in vitro. Moreover, IL-11 activates STAT3 signaling pathway to critically up-regulate TIMP-1 expression, as a consecutive secondary cellular response after IL-11 induction by LfcinB-ERK-AP-1 axis in human adult articular chondrocytes. The pathological relevance of IL-11 signaling to osteoarthritis is evidenced by significant down-regulation of its cognate receptor expression in osteoarthritic chondrocytes. Together, our results suggest a two-step mechanism, whereby LfcinB induces TIMP-1 through an IL-11-dependent pathway involving transcription factor AP-1 and STAT3.
authors.affiliation: From the Departments of Biochemistry.
authors.forename: Dongyao
authors.initials: D
authors.lastname: Yan
authors.forename: Ranjan
authors.initials: R
authors.lastname: Kc
authors.forename: Di
authors.initials: D
authors.lastname: Chen
authors.forename: Guozhi
authors.initials: G
authors.lastname: Xiao
authors.forename: Hee-Jeong
authors.initials: HJ
authors.lastname: Im
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002358:Cartilage, Articular; D002417:Cattle; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D017370:Interleukin-11 / Q000096:biosynthesis*; D007781:Lactoferrin / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010003:Osteoarthritis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000893:Anti-Inflammatory Agents; C508611:IL11 protein, human; D017370:Interleukin-11; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C560822:TIMP1 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; D018808:Transcription Factor AP-1; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D007781:Lactoferrin
keywords: Articular Cartilage; Chondrocytes; Gene Regulation; Interleukin; Osteoarthritis; Signal Transduction
references.citation: Nucleic Acids Res. 1995 Dec 25;23(24):5041-7
references.pmid: 8559663
references.citation: J Biol Chem. 2007 Oct 26;282(43):31409-21
references.pmid: 17724016
references.citation: J Cell Physiol. 2013 Feb;228(2):447-56
references.pmid: 22740381
references.citation: J Biol Chem. 2010 Jul 16;285(29):22414-25
references.pmid: 20463008
references.citation: Arthritis Rheum. 2010 Jul;62(7):2004-12
references.pmid: 20506365
references.citation: Arthritis Res. 2001;3(4):247-52
references.pmid: 11438043
references.citation: Osteoarthritis Cartilage. 2005 Oct;13(10):879-86
references.pmid: 15961329
references.citation: Gene. 2013 Jul 25;524(2):282-91
references.pmid: 23644135
references.citation: Mol Pharmacol. 2007 Sep;72(3):695-703
references.pmid: 17550983
references.citation: Semin Cell Dev Biol. 2001 Apr;12(2):69-78
references.pmid: 11292372
references.citation: Cell. 2010 May 28;141(5):884-96
references.pmid: 20493519
references.citation: J Biol Chem. 1998 Mar 6;273(10):5506-13
references.pmid: 9488674
references.citation: J Immunol. 1997 Dec 1;159(11):5661-70
references.pmid: 9548510
references.citation: Cytokine. 2005 Jan 21;29(2):72-6
references.pmid: 15598441
references.citation: Curr Rheumatol Rep. 2000 Dec;2(6):459-65
references.pmid: 11123098
references.citation: Kidney Int. 2003 Aug;64(2):459-67
references.pmid: 12846741
references.citation: Gene. 2013 Mar 15;517(1):12-8
references.pmid: 23313877
references.citation: J Med Virol. 2004 Oct;74(2):262-71
references.pmid: 15332275
references.citation: J Infect Dis. 1999 Mar;179(3):734-7
references.pmid: 9952389
references.citation: Arthritis Res Ther. 2009;11(6):R165
references.pmid: 19889203
references.citation: Arthritis Rheum. 2005 Aug;52(8):2376-85
references.pmid: 16052547
references.citation: Immunology. 1998 Sep;95(1):31-7
references.pmid: 9767454
references.citation: J Biol Chem. 1993 Oct 15;268(29):21527-32
references.pmid: 8408003
references.citation: J Rheumatol. 1994 Feb;21(2):314-20
references.pmid: 8182643
references.citation: J Biol Chem. 2007 Apr 13;282(15):11110-21
references.pmid: 17311929
references.citation: Mol Cell Biol. 2003 Oct;23(19):7030-43
references.pmid: 12972619
references.citation: Ann Rheum Dis. 2001 Feb;60(2):150-7
references.pmid: 11156549
references.citation: J Cell Physiol. 2013 Sep;228(9):1884-96
references.pmid: 23460134
references.citation: J Biol Chem. 2005 Aug 19;280(33):29780-7
references.pmid: 15961395
references.citation: J Immunol. 1996 Oct 15;157(8):3627-34
references.pmid: 8871663
references.citation: J Cell Sci. 2004 Dec 1;117(Pt 25):5965-73
references.pmid: 15564374
references.citation: Osteoarthritis Cartilage. 1997 Jan;5(1):23-37
references.pmid: 9010876
references.citation: Am J Physiol Cell Physiol. 2008 May;294(5):C1146-57
references.pmid: 18367585
references.citation: Curr Opin Cell Biol. 1997 Apr;9(2):240-6
references.pmid: 9069263
references.citation: J Rheumatol. 1999 Apr;26(4):870-9
references.pmid: 10229409
references.citation: Arthritis Rheum. 1998 Aug;41(8):1388-97
references.pmid: 9704636
references.citation: Clin Rheumatol. 2010 May;29(5):451-5
references.pmid: 20108016
references.citation: Mol Cell Biol. 1998 Sep;18(9):5073-81
references.pmid: 9710591
references.citation: Nat Med. 2009 Sep;15(9):1072-6
references.pmid: 19684582