In vitro study of the potential role of guanidines in leukocyte functions related to atherogenesis and infection.
BACKGROUND
The blunted immune response upon stimulation in chronic renal failure (CRF) is often coupled to a baseline inflammatory status which has been related to atherogenesis. Uremic biologic fluids and several specific uremic retention solutes alter cell-mediated immune responses, as well as the interaction of calcitriol with the immune system.


METHODS
The present study evaluated the influence of different guanidino compounds on DNA synthesis, chemiluminescence production, and CD14 expression of undifferentiated and calcitriol-differentiated HL-60 cells. In a second setup, these guanidino compounds were evaluated for their specific effect on normal human leukocyte oxidative burst activity and tumor necrosis factor-alpha (TNF-alpha) expression.


RESULTS
First, several guanidino compounds elicited proinflammatory effects on leukocytes. Methylguanidine and guanidine stimulated the proliferation of undifferentiated HL-60 cells and the antiproliferative effect of calcitriol (P < 0.05) was neutralized in the presence of methylguanidine (P < 0.05) and guanidinosuccinic acid (P < 0.05). The phorbol-myristate-acetate (PMA)-stimulated chemiluminescence production of the calcitriol differentiated HL-60 cells was enhanced in the presence of guanidine (P < 0.05). Methylguanidine and guanidinoacetic acid enhanced the lipopolysaccharide (LPS)-stimulated intracellular production of TNF-alpha by normal human monocytes (P < 0.05). Second, several guanidino compounds inhibited the function of leukocytes if they were activated. The PMA-stimulated chemiluminescence production of the calcitriol differentiated HL-60 cells was inhibited by the presence of methylguanidine (P < 0.05), guanidinoacetic acid (P < 0.05) and guanidinosuccinic acid (P < 0.05). After incubation of whole blood in the presence of methylguanidine, the Escherichia coli stimulated oxidative burst activity of the granulocyte population was significantly inhibited (P < 0.05). In addition, guanidinosuccinic acid had an inhibitory effect on the LPS-stimulated intracellular production of TNF-alpha by human monocytes (P < 0.01).


CONCLUSIONS
Guanidino compounds exert proinflammatory as well as anti-inflammatory effects on monocyte/macrophage function. This could contribute to the altered prevalence of cardiovascular disease and propensity to infection in patients with CRF.
Glorieux
Griet L
GL
Department of Internal Medicine, Renal Division, University Hospital, De Pintelaan, Ghent, Belgium. griet.glorieux@UGent.be
Dhondt
Annemieke W
AW
Jacobs
Peter
P
Van Langeraert
Joke
J
Lameire
Norbert H
NH
De Deyn
Peter Paul
PP
Vanholder
Raymond C
RC
D001161:Arteriosclerosis / Q000209:etiology*; D004247:DNA / Q000096:biosynthesis; D006146:Guanidines / Q000378:metabolism / Q000633:toxicity*; D018922:HL-60 Cells; D006801:Humans; D066298:In Vitro Techniques; D007239:Infections / Q000209:etiology*; D007962:Leukocytes / Q000187:drug effects* / Q000502:physiology*; D049449:Luminescence; D016897:Respiratory Burst / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D006146:Guanidines; D004247:DNA; D013755:Tetradecanoylphorbol Acetate