Modulation of Endothelial Cell Function by Normal Polyspecific Human Intravenous Immunoglobulins

Abstract

Intravenous immunoglobulin (IVIg) is increasingly used in the treatment of autoimmune and inflammatory diseases, including vasculitides and Kawasaki disease. However, the outcome of IVIg interaction with endothelial cells of the vascular bed is not clear as yet. We have investigated the effect of IVIg on the in vitro activation of human endothelial cells, as assessed by cell proliferation and reverse transcription-polymerase chain reaction-detected expression of mRNA coding for adhesion molecules (intercellular adhesion molecule-1 and vascular cellular adhesion molecule-1), chemokines (monocyte chemoattractant protein-1, macrophage colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor), and proinflammatory cytokines (tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6). IVIg inhibited proliferation of endothelial cells in a time-dependent manner. This effect was dependent on both Fc and F(ab')2 fragments of the immunoglobulin molecule and was fully reversible. Tumor necrosis factor-alpha and interleukin-1beta also inhibited thymidine incorporation, but to a lesser degree. IVIg had no effect on basal levels of mRNA coding for the adhesion molecules, chemokines, and proinflammatory cytokines. IVIg fully down-regulated the expression induced by tumor necrosis factor-alpha or interleukin-1beta of mRNA coding for these molecules. Thus, blockade of cellular proliferation and of cytokine-induced expression of adhesion molecules, chemokines, and cytokines may explain the therapeutic effect of IVIg in vascular and inflammatory disorders.

Anti‐inflammatory effects of high‐dose IgG on TNF‐α‐activated human coronary artery endothelial cells

“…[31] and we used 15 mg/mL and 20 mg/mL, respectively, while Xu et al [32] used 40 mg/mL. Importantly, our previous work [33] and that of others [34] demonstrated that the responses to cytokines and growth factors differ among various endothelial cell types depending on their origins.…”

“…These findings are compatible with our data that high-dose IgG had no effect on TNF-α-induced ICAM-1 expression in HCAECs (data not shown). On the other hand, Xu et al [32] found that IVIG downregulated the expression induced by both TNF-α and IL-1β of mRNA coding for some proinflammatory molecules, including ICAM-1, IL-6, and IL-1β. The discrepancy among these different studies may be due to the difference in the IgG concentrations used: Macmillan et al [31] and we used 15 mg/mL and 20 mg/mL, respectively, while Xu et al [32] used 40 mg/mL.…”

“…On the other hand, Xu et al [32] found that IVIG downregulated the expression induced by both TNF-α and IL-1β of mRNA coding for some proinflammatory molecules, including ICAM-1, IL-6, and IL-1β. The discrepancy among these different studies may be due to the difference in the IgG concentrations used: Macmillan et al [31] and we used 15 mg/mL and 20 mg/mL, respectively, while Xu et al [32] used 40 mg/mL. Importantly, our previous work [33] and that of others [34] demonstrated that the responses to cytokines and growth factors differ among various endothelial cell types depending on their origins.…”

“…Previously, several papers reported on the effects of IVIG on human umbilical vein endothelial cells (HUVECs) [31,32]. Macmillan et al demonstrated that IVIG completely inhibited neutrophil adhesion to HUVECs stimulated with IL-1α.…”

“…They develop CALs more frequently than responsive patients [26], and the cause of their nonresponsiveness remains unclear. However, previous studies by others suggested an association between IL-1β secretion and IVIG treatment in KD patients [27,28] Previously, several papers reported on the effects of IVIG on human umbilical vein endothelial cells (HUVECs) [31,32]. Macmillan et al demonstrated that IVIG completely inhibited neutrophil adhesion to HUVECs stimulated with IL-1α.…”