In vitro study of the potential role of guanidines in leukocyte functions related to atherogenesis and infection.

Abstract

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).

CONCLUSION:

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.

• Authors: Griet L Glorieux, Annemieke W Dhondt, Peter Jacobs, Joke Van Langeraert, Norbert H Lameire, Peter Paul De Deyn, Raymond C Vanholder
• Journal: Kidney international (Kidney Int) Vol. 65 Issue 6 Pg. 2184-92 (Jun 2004) ISSN: 0085-2538 [Print] United States
• PMID: 15149331 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Guanidines
• DNA
• Tetradecanoylphorbol Acetate

Topics

• Arteriosclerosis (etiology)
• DNA (biosynthesis)
• Guanidines (metabolism, toxicity)
• HL-60 Cells
• Humans
• In Vitro Techniques
• Infections (etiology)
• Leukocytes (drug effects, physiology)
• Luminescence
• Respiratory Burst (drug effects)
• Tetradecanoylphorbol Acetate (pharmacology)