Thalidomide inhibits inflammatory and angiogenic activation of human intestinal microvascular endothelial cells (HIMEC)

Abstract

The glutamic acid derivative thalidomide is a transcriptional inhibitor of TNF-alpha but is also known to affect human blood vessels, which may underlie its teratogenicity. Thalidomide has been used in the treatment of refractory Crohn's disease (CD), but the therapeutic mechanism is not defined. We examined the effect of thalidomide on primary cultures of human intestinal microvascular endothelial cells (HIMEC), the relevant endothelial cell population in inflammatory bowel disease (IBD), to determine its effect on endothelial activation, leukocyte interaction, and VEGF-induced angiogenesis. HIMEC cultures were pretreated with thalidomide before activation with either TNF-alpha/LPS or VEGF. A low-shear-stress flow adhesion assay with either U-937 or whole blood was used to assess HIMEC activation following TNF-alpha/LPS, and a Wright's stain identified adherent leukocytes. Expression of cell adhesion molecules (E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1) was assessed using radioimmunoassay. Effects of thalidomide on NF-kappaB activation, cyclooxygenase (COX)-2, and inducible nitric oxide synthase (iNOS) expression in TNF-alpha/LPS-activated HIMEC were determined by RT-PCR and Western blotting. Thalidomide blocked adhesion of both U-937 and whole blood leukocytes by 50% in HIMEC, inhibiting binding of all classes of leukocytes. Thalidomide also blocked NF-kappaB and cell adhesion molecule expression in HIMEC. In marked contrast, thalidomide did not affect either iNOS or COX-2 expression, two key molecules that play a role in the downregulation of HIMEC activation. VEGF-induced HIMEC transmigration, growth, proliferation, tube formation, and Akt phosphorylation were significantly inhibited by thalidomide. In summary, thalidomide exerted a potent effect on HIMEC growth and activation, suggesting that it may also function via an endothelial mechanism in the treatment of CD.

Lenalidomide Restrains Motility and Overangiogenic Potential of Bone Marrow Endothelial Cells in Patients with Active Multiple Myeloma

“…In fact, as shown here, lenalidomide is antiangiogenic in vivo (CAM assay) and in vitro, hence overlapping thalidomide (37,38). However, lenalidomide halts only MMEC chemotaxis but not proliferation whereas thalidomide halts both EC functions (38) and MMEC proliferation (10). Tentatively, we suggest that the differential effects of the drug may derive from distinct mechanisms of action at the molecular level: thalidomide potently inhibits EC functions, possibly through preventing Erk-1/2 nuclear translocation and/or inhibition of Akt/PKB phophorylation, thus halting mainly VEGF-mediated survival/proliferation (38) whereas lenalidomide inhibits markedly MLC phosphorylation in the cytoplasm (Supplementary Fig.…”

“…Thus, each molecule cannot be assumed to have the same overall biological effects or therapeutic properties as thalidomide or other IMiDs. In fact, as shown here, lenalidomide is antiangiogenic in vivo (CAM assay) and in vitro, hence overlapping thalidomide (37,38). However, lenalidomide halts only MMEC chemotaxis but not proliferation whereas thalidomide halts both EC functions (38) and MMEC proliferation (10).…”

Thalidomide plus chemotherapy exhibit enhanced efficacy in the clinical treatment of T-cell non-Hodgkin’s lymphoma: A prospective study of 46 cases

“…Thalidomide inhibits the secretion of basic fibroblast growth factor, an angiogenic factor secreted by human tumors (28), thus reducing tumor-associated macrophage infiltration, possibly through suppressing the expression of endothelial cell adhesion molecules (29). Thalidomide also suppresses TNF-α-induced intercellular adhesion molecule-1 expression through inhibiting nuclear factor-κB (30).…”

Severe exacerbation of Crohn’s disease during sunitinib treatment

“…Also, thalidomide has effectively been used as therapy in Crohn's disease [9,10]. Besides its immunomodulatory effect through inhibition of tumor necrosis factor-a production, thalidomide has also been shown to have antiangiogenic properties [11,12]. However, whether the positive effect of thalidomide on disease activity in Crohn's disease is attributable to antiangiogenic properties or to immunomodulatory effects has yet to be elucidated.…”