Hypoxic induction of interleukin-8 gene expression in human endothelial cells.

Abstract

Because leukocyte-mediated tissue damage is an important component of the pathologic picture in ischemia/reperfusion, we have sought mechanisms by which PMNs are directed into hypoxic tissue. Incubation of human endothelial cells (ECs) in hypoxia, Po2 -14-18 Torr, led to time-dependent release of IL-8 antigen into the conditioned medium; this was accompanied by increased chemotactic activity for PMNs, blocked by antibody to IL-8. Production of IL-8 by hypoxic ECs occurred concomitantly with both increased levels of IL-8 mRNA, based on polymerase chain reaction analysis, and increased IL-8 transcription, based on nuclear run-on assays. Northern analysis of mRNA from hypoxic ECs also demonstrated increased levels of mRNA for macrophage chemotactic protein-i, another member of the chemokine superfamily of proinflammatory cytokines. IL-8 gene induction was associated with the presence of increased binding activity in nuclear extracts from hypoxic ECs for the NF-kB site. Studies with human umbilical vein segments exposed to hypoxia also demonstrated increased elaboration of IL-8 antigen compared with normoxic controls. In mice exposed to hypoxia (Po2 30-40 Torr), there was increased pulmonary leukostasis, as evidenced by increased myeloperoxidase activity in tissue homogenates. In parallel, increased levels of transcripts for IP-10, a murine homologue in the chemokine family related to IL-8, were observed in hypoxic lung tissue. Taken together, these data suggest that hypoxia constitutes a stimulus for leukocyte chemotaxis and tissue leukostasis. (J. Clin. Invest. 1994. 93:1564-1570

Chemokines in High Altitude Pulmonary Edema

“…Indeed hypoxia exposure whether, in vitro or in vivo, is associated with rise in inflammatory markers. However, in the previous studies, as also quoted in the article by the authors, the duration of hypoxia exposure varied from 16 to 72 h [2][3][4][5] On the contrary, in the present study duration of simulated hypoxia of 4500 m was only 30 min. It remains obscure that those changes seen in the chemokines are actually the result of hypoxia induced inflammation or otherwise.…”

Regulation of interleukin-8 expression by reduced oxygen pressure in human glioblastoma

“…It is also possible that in vivo in¯ammatory cells such as microglia or macrophages participate in IL-8 expression since anoxia can stimulate them to release IL-8 (Metinko et al, 1992). Tumor microvascular cells were not found to express IL-8, although endothelial cells can synthesize IL-8 in response to hypoxia (Karakurum et al, 1994;Stevens and Rodman, 1995;Ziesche et al, 1996). Despite the fact that hypoxia stimulates the release of IL-8 and facilitates polymorphonuclear leukocytes (PMN) transmigration (Colgan et al, 1996), PMN in®ltrates are rarely found in glioblastoma sections.…”

Endothelial damage caused by cytomegalovirus and human herpesvirus-6

“…1 Immunosuppressants, acute graft-versus-host disease (GVHD), viral infection, and steroids have been reported as possible risk factors for secondary clinical manifestations of TMA after BMT, but the pathogenesis is still unknown. [2][3][4][5][6] However, some information concerning possible secondary clinical manifestations of TMA [7][8][9][10] and an association between vascular endothelium damage and increased levels of cytokines 11 as well as chemokines 12,13 has been reported.…”