Endotoxins induce and interferon alpha suppresses vascular endothelial growth factor (VEGF) production in human peripheral blood mononuclear cells.

Abstract

Endotoxins, classical activators of innate immune cells, induce systemic inflammation designated by increased microvascular permeability, and, not so infrequently, circulatory shock, organ dysfunction, and death. Vascular endothelial growth factor (VEGF), besides being an endothelial-cell mitogen, is a strong vascular permeability factor. This study demonstrates that peripheral blood mononuclear cells (PBMNCs) from healthy volunteers cultured in serum-free medium in the absence of any stimulus release VEGF continuously into culture media. Physiological endotoxin concentrations stimulate this VEGF secretion in a dose-dependent manner, representing an induction of de novo VEGF production, as an induction of the expression of the major 3.7-kb VEGF mRNA transcripts was observed, and the release of VEGF was blocked by cycloheximide. Reverse transcription-polymerase chain reaction also verified the expression of the four VEGF transcripts. Interferon-α, a modulator of the immune system and an inhibitor of angiogenesis, inhibited VEGF release dose dependently. We conclude that endotoxin promotes VEGF production in PBMNCs. Circulating and emigrating VEGF-producing PBMNCs may enhance the shift to angiogenic phenotype in a variety of infectious and inflammatory disorders as well as in cancer. VEGF-producing PBMNCs may be a novel mechanism of tissue edema in systemic inflammation. Inhibition of VEGF production in PBMNCs may be one of the mechanisms of interferon-α action.