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Comment on “A Novel Role of Hypoxia-Inducible Factor in Cobalt Chloride- and Hypoxia-Mediated Expression of IL-8 Chemokine in Human Endothelial Cells”1

I n their recent article, Kim et al. (1) demonstrated that activation of hypoxia-inducible factor-1 (HIF-1) transcription factor by hypoxia (1% O2) or CoCl2, a hypoxiamimic, can induce IL-8 mRNA and protein expressions in various human endothelial cells, namely dermal vascular (HDMVEC), pulmonary microvascular (HPMVEC), brain (HBEC), and pulmonary aortic (HPAEC), an observation similar to that of previous, but uncited, investigators (2). The majority of the present experiments has been done in HDMVEC. However, our recently published data indicate that the underlying mechanisms may be more complex. In our experiments done in immortalized HDMVEC line HMEC-1, we have observed that neither hypoxia (3) nor CoCl2 (4) induces IL-8 expression. In fact, the effect of hypoxia (1% O2) on both IL-8 mRNA and protein expression was inhibitory (3). In addition, CoCl2 was not able to enhance the expression of IL-8 (4), although it increased HIF-1 activation and synthesis of vascular endothelial growth factor to the same level as hypoxia (3, 4). Thus, our data point to the other mechanisms of regulation of IL-8 than that demonstrated by Kim et al. Moreover, in another recent article (5), activation of HIF-1 by prolyl hydroxylase inhibitor attenuated IL-8 production in HMEC-1. Interestingly, the negative role of HIF-1 in regulation of IL-8 expression also has been demonstrated recently in several tumor cell lines (6), whereas another study showed that desferoxamine, an activator of HIF-1, decreased TNF-induced IL-8 synthesis in HDMVEC (7). The reasons for such different data are not clear. First, the cell-type specific effect may exist. However, it seems that HDMVEC used by Kim et al., which were provided to them by Drs. Ades and Lawley, might be in fact the same as the HMEC-1 line (8) used by us (3, 4) and others (5, 7). Second, the concentrations of CoCl2 used by Kim et al. to stimulate IL-8 expression were very high, i.e., 0.5-1 mM. Both in our hands (4) and in Ockaili et al. experiments (5), much lower concentrations, i.e., 0.1-0.25 mM, of CoCl2 potently stabilized HIF-1 and activated a hypoxia-responsive element in reporter gene assays. However, such low concentration of CoCl2 did not affect IL-8 production, although it potently enhanced HIF-1dependent vascular endothelial growth factor synthesis by HMEC-1 to the level exerted by hypoxia (3, 4). In fact, 0.25 mM CoCl2 was also not effective in the work of Kim et al. (1). Finally, in our hands, 1% O2 down-regulated IL-8 mRNA expression and protein synthesis after 24 h of culture. In turn, Kim et al. measured IL-8 production only after 6 h of hypoxia (description to Fig. 3 states this time, although in the text the authors mentioned 24 h, recalling the same figure) and observed only an 1.6-fold increase in protein synthesis. Thus, the influence of HIF-1 and hypoxia on IL-8 production is far from clear. Which effects reflect the physiological conditions remain to be elucidated.