title: C5a stimulates production of plasminogen activator inhibitor-1 in human mast cells and basophils.
abstract: We have recently shown that resting human mast cells (MCs) produce tissue-type plasminogen activator (t-PA) without simultaneously expressing plasminogen activator inhibitor 1 (PAI-1). In the present study we have identified the anaphylatoxin rhC5a as a potent inducer of PAI-1 expression in human MCs and basophils. In primary human skin MCs and primary blood basophils, exposure to rhC5a was followed by an increase from undetectable to significant levels of PAI-1. In addition, rhC5a induced a concentration- and time-dependent increase in PAI-1 antigen in the MC line HMC-1 and the basophil cell line KU-812 and increased the expression of PAI-1 mRNA in HMC-1. In conditioned media of HMC-1 treated with rhC5a, active PAI-1 could be detected. A simultaneous loss of t-PA activity in conditioned media from the same cells indicated that rhC5a-induced PAI-1 was capable of inhibiting the enzymatic activity of coproduced t-PA. Correspondingly, the levels of t-PA-PAI-1 complexes increased in rhC5a-treated cells. When HMC-1 cells were incubated with pertussis toxin or anti-C5a receptor antibodies, the effect of rhC5a on PAI-1 production was completely abolished. Treatment of C5a with plasmin resulted in loss of its ability to induce PAI-1 production in MCs. Considering the suggested role for MCs and components of the complement system in the development of cardiovascular diseases, we hypothesize that MCs, by producing t-PA in a resting state and by expressing PAI-1 when activated by C5a, might participate in the modulation of the balance between proteases and protease inhibitors regulating tissue injury and repair in such disease processes.
authors.affiliation: Department of Internal Medicine II, University of Vienna, Austria. johann.wojta@univie.ac.at
authors.forename: Johann
authors.initials: J
authors.lastname: Wojta
authors.forename: Christoph
authors.initials: C
authors.lastname: Kaun
authors.forename: Gerlinde
authors.initials: G
authors.lastname: Zorn
authors.forename: Minoo
authors.initials: M
authors.lastname: Ghannadan
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Hauswirth
authors.forename: Wolfgang R
authors.initials: WR
authors.lastname: Sperr
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fritsch
authors.forename: Dieter
authors.initials: D
authors.lastname: Printz
authors.forename: Bernd R
authors.initials: BR
authors.lastname: Binder
authors.forename: Georg
authors.initials: G
authors.lastname: Schatzl
authors.forename: Joerg
authors.initials: J
authors.lastname: Zwirner
authors.forename: Gerald
authors.initials: G
authors.lastname: Maurer
authors.forename: Kurt
authors.initials: K
authors.lastname: Huber
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
mesh_terms: D015703:Antigens, CD / Q000502:physiology; D001491:Basophils / Q000187:drug effects / Q000378:metabolism*; D001773:Blood Cells / Q000166:cytology; D002460:Cell Line; D015936:Complement C5a / Q000494:pharmacology* / Q000502:physiology; D005341:Fibrinolysin / Q000494:pharmacology; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000819:agonists / Q000096:biosynthesis*; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000502:physiology; D012867:Skin / Q000166:cytology; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D015703:Antigens, CD; D017395:Plasminogen Activator Inhibitor 1; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D015936:Complement C5a; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin