Inflammatory cytokines regulate endothelial cell survival and tissue repair functions via NF-κB signaling

Abstract

Inflammation contributes to the development of fibrotic and malignant diseases. We assessed the ability of inflammatory cytokines to modulate endothelial cell survival and functions related to tissue repair/remodeling. Treatment with interleukin (IL)-1β or tumor necrosis factor (TNF)-α (2 ng/mL) led to human pulmonary artery endothelial cells becoming spindle-shaped fibroblast-like cells. However, immunoblot and DNA microarray showed no change in most endothelial and mesenchymal markers. In the presence of IL-1β or TNF-α, cells were resistant to apoptosis induced by deprivation of serum and growth factor, and were more migratory. In addition, cells treated with IL-1β or TNF-α contracted collagen gels more robustly. In contrast, transforming growth factor-β1 did not induce these responses. RNA interference targeting nuclear factor (NF)-κB p65 blocked the effects of IL-1β or TNF-α on cell morphologic change, survival, migration, and collagen gel contraction. These results suggest that endothelial cells may contribute to tissue repair/remodeling via the NF-κB signaling in a milieu of airway inflammation.

Differential Roles of JNK, ERK1/2, and p38 Mitogen-Activated Protein Kinases on Endothelial Cell Tissue Repair Functions in Response to Tumor Necrosis Factor-α

“…We have previously reported that inflammatory cytokines IL-1β and TNF-α modulate endothelial cell survival through p65 activation [4] and that p38 modulates endothelial cell survival and tissue repair function in response to IL-1β stimulation [17]. In the current study, we further report that TNF-α also induced MAPK (ERK, JNK, and p38) activation; furthermore, MAPK kinase inhibitors can also modulate endothelial cell survival.…”

“…We recently reported that TNF-α can promote HPAEC survival and tissue repair functions including wound closure and collagen gel contraction [4]. The mechanism by which the effect of TNF-α is mediated, however, has not been defined.…”

“…First, we did not investigate any downstream signaling from the MAPKs that may be responsible for cell survival (for instance, caspases and Bcl-2 family proteins) and tissue repair functions altered by TNF-α. Second, we did not assess cross talk among MAPKs, although the activity of one MAPK can be influenced by another [34] or interplay between NF-ĸB and MAPK signaling pathways although we have reported that NF-ĸB also play a role in modulating endothelial cell survival and functions [4]. Third, we used only one type of endothelial cells.…”

“…In combination with the release of chemokines, these responses lead to recruitment of leukocytes, which can promote inflammation [2]. TNF-α can also alter endothelial cell functions such as migration and survival, and by these mechanisms TNF-α may contribute to the development of fibrosis by modulating tissue repair/remodeling [3,4,5,6]. …”

“…Recently, it was reported that MAPKs are involved in corneal endothelium defect repair [16]. In addition, we recently reported that TNF-α promotes tissue repair/remodeling via NF-ĸB signaling in human pulmonary artery endothelial cells (HPAECs) [4], and that p38 MAPK modulates endothelial cell survival and tissue repair in response to IL-1β stimulation [17]. …”