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-α [TNF-α], or IL-1α) 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.

Activated platelets mediate inflammatory signaling by regulated interleukin 1β synthesis

“…2 A, top right). The result is consistent with previous reports that IL-1 ␤ activity is present in stimulated platelets (Hawrylowicz et al, 1989;Loppnow et al, 1998). Pretreatment of platelets with puromycin, a translational inhibitor, completely inhibited IL-1 ␤ synthesis (Fig.…”

“…Accumulation of IL-1 ␤ is prolonged, attenuated by blocking engagement of ␤ 3 integrins, and mediates signaling of endothelial cells with consequent neutrophil (polymorphonuclear leukocyte [PMN]) adhesion. It was reported earlier that stimulated platelets possess IL-1 ␤ activity, but they were not thought to actively synthesize this inflammatory protein (Hawrylowicz et al, 1989;Loppnow et al, 1998). Regulated cytokine synthesis establishes the potential for previously unrecognized biologic roles for platelets in inflammation and vascular injury.…”

Growth factors and cytokines in autologous platelet concentrate and their correlation to periodontal regeneration outcomes

“…As suggested by other studies (Loppnow et al 1998, Gruber et al 2002), cytolysis of the platelets was achieved by ultrasonics. In contrast, Weibrich et al (2002a, c, d, 2003a) and Landesberg et al (2000) centrifuged their samples for cytolysis.…”

Circulating interleukin‐6 predicts survival in patients with metastatic breast cancer

“…In previous studies it has been shown that circulating VEGF resides mostly in platelets 42, 46, 47. Whether serum IL‐6 also accounts for platelet residing IL‐6 is discerned by the fact that platelets have neither the mRNA nor the protein of IL‐6 48, 49. These and other data suggest that both tumour cells as well as stromal and inflammatory cells, are responsible for the increased serum levels of IL‐6 in cancer patients.…”