title: Platelet-derived interleukin-1 induces cytokine production, but not proliferation of human vascular smooth muscle cells.
abstract: During vascular injury, such as observed in atherosclerosis, restenosis, vasculitides, transplantation, or sepsis, vascular smooth muscle cells (SMC) can be exposed to platelets or platelet products. Under these conditions proliferation or cytokine production of SMC stimulated by platelets or platelet products may contribute to regulation of vascular pathogenesis. Thus, we investigated interleukin-6 (IL-6) and IL-8 production as well as proliferation of SMC in response to platelets or platelet lysates. Platelets not already preactivated by thrombin induced IL-6 (10- to 50-fold) or IL-8 production of unstimulated SMC in a cell number dependent fashion. Preactivation of platelets with thrombin potently increased the platelet-mediated IL-6 (50- to 1,000-fold) and IL-8 production of SMC. Hirudin specifically inhibited the activation of platelets with thrombin. Isolated platelets cultured in the absence of SMC did not contain detectable IL-6 or IL-8. Prestimulation (4 hours) of SMC with pathophysiologically relevant substances (lipopolysaccharide [LPS], tumor necrosis factor-alpha [TNF-alpha], or IL-1alpha) further increased the platelet-induced cytokine production. The platelet-derived SMC stimulatory activity was IL-1, since IL-1 receptor antagonist (IL-1-Ra) inhibited the platelet-induced cytokine production of SMC. Anti-platelet-derived growth factor (PDGF)-antibody did not further reduce this activity. Thrombin itself stimulated expression of IL-6 and IL-8 to some degree and induced IL-6 production of SMC synergistically with IL-1. Platelets also induced proliferation of SMC, however, anti-PDGF antibodies, rather than IL-1-Ra blocked this response. These data show that platelet-derived IL-1 stimulates cytokine production of vascular smooth muscle cells, indicating that platelet-derived IL-1 may contribute to regulation of local pathogenesis in the vessel wall by activation of the cytokine regulatory network.
authors.affiliation: Forschungszentrum Borstel, Zentrum für Medizin und Biowissenschaften, Borstel, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Loppnow
authors.forename: R
authors.initials: R
authors.lastname: Bil
authors.forename: S
authors.initials: S
authors.lastname: Hirt
authors.forename: U
authors.initials: U
authors.lastname: Schönbeck
authors.forename: M
authors.initials: M
authors.lastname: Herzberg
authors.forename: K
authors.initials: K
authors.lastname: Werdan
authors.forename: E T
authors.initials: ET
authors.lastname: Rietschel
authors.forename: E
authors.initials: E
authors.lastname: Brandt
authors.forename: H D
authors.initials: HD
authors.lastname: Flad
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D001792:Blood Platelets / Q000737:chemistry / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D005786:Gene Expression Regulation / Q000187:drug effects; D006629:Hirudins / Q000494:pharmacology; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000494:pharmacology / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D012795:Sialoglycoproteins / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000911:Antibodies, Monoclonal; D006629:Hirudins; C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D008070:Lipopolysaccharides; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D013917:Thrombin