title: Interleukin-6 synthesis in human chondrocytes is regulated via the antagonistic actions of prostaglandin (PG)E2 and 15-deoxy-Δ(12,14)-PGJ2.
abstract: BACKGROUND
  Elevated levels of interleukin-6 (IL-6), prostaglandin (PG)E(2), PGD(2) and its dehydration end product 15-deoxy-Δ(12,14)-PGJ(2) (15d-PGJ(2)) have been detected in joint synovial fluids from patients with rheumatoid arthritis (RA). PGE(2) directly stimulates IL-6 production in human articular chondrocytes. However, the effects of PGD(2) and 15d-PGJ(2) in the absence or presence of PGE(2) on IL-6 synthesis in human chondrocytes have yet to be determined. It is believed that dysregulated overproduction of IL-6 is responsible for the systemic inflammatory manifestations and abnormal laboratory findings in RA patients.
  
  
  RESULTS
  Using the T/C-28a2 chondrocyte cell line as a model system, we report that exogenous PGE(2) and PGD(2)/15d-PGJ(2) exert antagonistic effects on IL-6 synthesis in human T/C-28a2 chondrocytes. Using a synthesis of sophisticated molecular biology techniques, we determined that PGE(2) stimulates Toll-like receptor 4 (TLR4) synthesis, which is in turn responsible for the activation of the ERK1/2, PI3K/Akt and PKA/CREB pathways that phosphorylate the NF-κB p65 subunit leading to NF-κB activation. Binding of the activated NF-κB p65 subunit to IL-6 promoter induces IL-6 synthesis in human T/C28a2 chondrocytes. PGD(2) or 15d-PGJ(2) concurrently downregulates TLR4 and upregulates caveolin-1, which in turn inhibit the PGE(2)-dependent ERK1/2, PI3-K and PKA activation, and ultimately with NF-κB-dependent IL-6 synthesis in chondrocytes.
  
  
  CONCLUSIONS
  We have delineated the signaling cascade by which PGE(2) and PGD(2)/15d-PGJ(2) exert opposing effects on IL-6 synthesis in human chondrocytes. Elucidation of the molecular pathway of IL-6 synthesis and secretion by chondrocytes will provide insights for developing strategies to reduce inflammation and pain in RA patients.
authors.affiliation: Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Pu
authors.initials: P
authors.lastname: Wang
authors.forename: Fei
authors.initials: F
authors.lastname: Zhu
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Konstantopoulos
mesh_terms: D051242:Caveolin 1 / Q000378:metabolism; D002460:Cell Line; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism*; D015232:Dinoprostone / Q000494:pharmacology*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D051242:Caveolin 1; D015850:Interleukin-6; D016328:NF-kappa B; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D019869:Phosphatidylinositol 3-Kinases; D015232:Dinoprostone; D015230:Prostaglandin D2
references.citation: J Bone Miner Res. 1992 Apr;7(4):397-404
references.pmid: 1319104
references.citation: Z Rheumatol. 1984 Mar-Apr;43(2):89-96
references.pmid: 6730731
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 27;102(39):14010-5
references.pmid: 16172382
references.citation: J Neuroimmunol. 2010 Jan 25;218(1-2):36-47
references.pmid: 19942298
references.citation: J Clin Invest. 1996 Jun 1;97(11):2672-9
references.pmid: 8647962
references.citation: J Clin Invest. 1997 Mar 15;99(6):1231-7
references.pmid: 9077531
references.citation: Br J Pharmacol. 2002 May;136(2):287-95
references.pmid: 12010778
references.citation: Am J Physiol Cell Physiol. 2008 May;294(5):C1146-57
references.pmid: 18367585
references.citation: Osteoarthritis Cartilage. 2010 Apr;18(4):581-92
references.pmid: 20060954
references.citation: Int J Biochem Cell Biol. 2008;40(4):677-88
references.pmid: 18035585
references.citation: J Cancer Res Clin Oncol. 2009 Mar;135(3):379-86
references.pmid: 18825409
references.citation: PLoS Pathog. 2007 Apr;3(4):e60
references.pmid: 17465679
references.citation: Arthritis Rheum. 2008 Nov;58(11):3530-40
references.pmid: 18975308
references.citation: Cell Death Differ. 2010 Aug;17(8):1325-34
references.pmid: 20150912
references.citation: Mod Rheumatol. 2006;16(1):3-13
references.pmid: 16622717
references.citation: Cell Mol Life Sci. 1999 Dec;56(11-12):945-70
references.pmid: 11212327
references.citation: Blood. 2008 Feb 15;111(4):1781-8
references.pmid: 18025155
references.citation: Endocrinology. 1996 Jun;137(6):2208-16
references.pmid: 8641167
references.citation: Arthritis Rheum. 2001 Mar;44(3):595-607
references.pmid: 11263774
references.citation: J Biol Chem. 2004 May 21;279(21):22399-403
references.pmid: 15004016
references.citation: Arthritis Rheum. 2009 Feb;60(2):513-23
references.pmid: 19180509
references.citation: J Immunol. 2006 Aug 1;177(3):1879-85
references.pmid: 16849500
references.citation: J Biol Chem. 2004 Aug 20;279(34):36103-11
references.pmid: 15199053
references.citation: J Clin Invest. 2002 Sep;110(5):651-8
references.pmid: 12208866
references.citation: J Immunol. 2000 Jan 15;164(2):1046-54
references.pmid: 10623855
references.citation: Arthritis Rheum. 2002 Jul;46(7):1789-803
references.pmid: 12124863
references.citation: Inflamm Res. 2006 Apr;55 Suppl 1:S73-4
references.pmid: 16547804
references.citation: J Biochem. 1999 Sep;126(3):553-8
references.pmid: 10467171
references.citation: Nat Immunol. 2003 Apr;4(4):313-9
references.pmid: 12660731
references.citation: Oncogene. 2003 Jun 19;22(25):3888-900
references.pmid: 12813462
references.citation: Proc Natl Acad Sci U S A. 2002 May 28;99(11):7367-72
references.pmid: 12032289
references.citation: Biochem Biophys Res Commun. 2000 Apr 13;270(2):400-5
references.pmid: 10753637
references.citation: Nat Immunol. 2004 Jan;5(1):98-103
references.pmid: 14661019
references.citation: Arthritis Rheum. 1988 Jun;31(6):784-8
references.pmid: 3260102
references.citation: J Clin Immunol. 2008 Sep;28(5):558-70
references.pmid: 18463970
references.citation: J Clin Invest. 1994 Dec;94(6):2307-16
references.pmid: 7989586
references.citation: Cell Host Microbe. 2007 Jun 14;1(4):287-98
references.pmid: 17710226
references.citation: Brain Res. 1997 Nov 28;777(1-2):210-8
references.pmid: 9449430
references.citation: Dig Dis Sci. 2006 Apr;51(4):693-7
references.pmid: 16614990
references.citation: J Biol Chem. 1999 Apr 30;274(18):12933-8
references.pmid: 10212284
references.citation: J Exp Med. 1996 Sep 1;184(3):883-91
references.pmid: 9064348
references.citation: J Immunol. 2009 Mar 15;182(6):3809-18
references.pmid: 19265160
references.citation: Clin Exp Pharmacol Physiol. 2005 Mar;32(3):230-2
references.pmid: 15743408
references.citation: Am J Physiol Cell Physiol. 2010 Jun;298(6):C1445-56
references.pmid: 20457835
references.citation: J Periodontal Res. 2002 Feb;37(1):29-36
references.pmid: 11842936
references.citation: Am J Physiol Cell Physiol. 2001 Oct;281(4):C1241-50
references.pmid: 11546661
references.citation: Semin Arthritis Rheum. 2003 Dec;33(3):155-67
references.pmid: 14671726
references.citation: J Biol Chem. 2010 Aug 6;285(32):24793-804
references.pmid: 20516073
references.citation: J Cell Biochem. 1998 Jun 15;69(4):392-413
references.pmid: 9620167
references.citation: Am J Physiol Heart Circ Physiol. 2010 Jan;298(1):H136-43
references.pmid: 19880670
references.citation: Scand J Rheumatol. 1977;6(3):151-4
references.pmid: 929121
references.citation: J Biol Chem. 2004 Sep 3;279(36):37939-50
references.pmid: 15213234
references.citation: PLoS One. 2010 Dec 29;5(12):e15174
references.pmid: 21209926
references.citation: J Biol Chem. 2003 Aug 1;278(31):28388-94
references.pmid: 12743126