title: IL-1 beta induces COX2, MMP-1, -3 and -13, ADAMTS-4, IL-1 beta and IL-6 in human tendon cells.
abstract: Overuse injuries and trauma in tendon often involve acute or chronic pain and eventual matrix destruction. Anti-inflammatory drugs have been used as a treatment, however, the cellular and molecular mechanisms of the destructive processes in tendon are not clearly understood. It is thought that an inflammatory event may be involved as an initiating factor. Mediators of the inflammatory response include cytokines released from macrophages and monocytes. Interleukin-1 beta (IL-1 beta) is a candidate proinflammatory cytokine that is active in connective tissues such as bone and cartilage. We hypothesized that tendon cells would express receptors and respond to IL-1 beta in an initial "molecular inflammation" cascade, that is, connective tissue cell expression of cytokines that induce matrix destructive enzymes. This cascade results in expression of matrix metalloproteinases (MMPs) and aggrecanases that may lead to matrix destruction. Normal human tendon cells from six patients were isolated, grown to quiescence and treated with human recombinant IL-1 beta in serum-free medium for 16 h. Total RNA was isolated and mRNA expression assessed by semiquantitative RT-PCR. IL-1 beta (1 nM) induced mRNAs for cyclooxygenase 2 (COX2), MMP-1, -3, -13 and aggrecanase-1 as well as IL-1 beta and IL-6, whereas mRNAs for COX1 and MMP-2 were expressed constitutively. The IL-1 beta-treated tendon cells released prostaglandin E(2) (PGE(2)) in the medium, suggesting that the inducible COX2 catalyzed this synthesis. Induction of PGE(2) was detectable at 10 pM IL-1 beta. IL-1 beta also stimulated MMP-1 and -3 protein secretion. Induction of MMP-1 and -3 was detectable at 10 pM IL-1 beta. Post-injury or after some other inciting events, exogenous IL-1 beta released upon bleeding or as leakage of local capillaries may drive a proinflammatory response at the connective tissue cell level. The resulting induction of COX2, MMP-1 and -3 may underscore a potential for nonlymphocyte-mediated cytokine production of MMPs that causes matrix destruction and a loss of tendon biomechanical properties. Endogenous IL-1 beta might contribute to the process through a positive feedback loop by stimulating expression and accumulation of MMPs in the tendon matrix.
authors.affiliation: Department of Orthopaedics, University of North Carolina, 277 Burnett-Womack Bldg., CB#7055, Chapel Hill, NC 27599-7055, USA. mari_tsuzaki@med.unc.edu
authors.forename: M
authors.initials: M
authors.lastname: Tsuzaki
authors.forename: G
authors.initials: G
authors.lastname: Guyton
authors.forename: W
authors.initials: W
authors.lastname: Garrett
authors.forename: J M
authors.initials: JM
authors.lastname: Archambault
authors.forename: W
authors.initials: W
authors.lastname: Herzog
authors.forename: L
authors.initials: L
authors.lastname: Almekinders
authors.forename: D
authors.initials: D
authors.lastname: Bynum
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.forename: A J
authors.initials: AJ
authors.lastname: Banes
mesh_terms: D051722:ADAM Proteins; D000071121:ADAMTS4 Protein; D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D017931:DNA Primers / Q000737:chemistry; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D025461:Feedback, Physiological / Q000502:physiology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008565:Membrane Proteins; D008666:Metalloendopeptidases / Q000096:biosynthesis* / Q000235:genetics; D008875:Middle Aged; D011348:Procollagen N-Endopeptidase; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013710:Tendons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology
chemical_list: D017931:DNA Primers; D007375:Interleukin-1; D015850:Interleukin-6; D007527:Isoenzymes; D008565:Membrane Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D011348:Procollagen N-Endopeptidase; D000071121:ADAMTS4 Protein; C000603918:ADAMTS4 protein, human; D015232:Dinoprostone