Hypoxia inducible factor-1 (HIF-1) is a transcription factor that is a major regulator of cellular adaption to low oxygen levels [
1,
2]. More recently, HIF has been recognized to play a role in host defense, promoting the bactericidal activity of phagocytic and epithelial cells and supporting innate immune activities of dendritic cells and mast cells [
3‐
6]. HIF is comprised of a constitutively expressed β subunit that partners with dynamically regulated α subunits (HIF-1α, HIF-2α, or HIF-3α), which are unstable under normoxic conditions [
7]. The short half-life of HIF-α subunits reflects the activity of a family of oxygen-and iron-dependent prolyl hydroxylases (PHDs), which direct HIF-α subunits to proteosomal degradation [
8]. A new PHD inhibitor, AKB-4924, acts as a HIF-1α stabilizing agent to increase HIF-1 levels and boosts the bactericidal activity of cultured phagocytes and skin cells against important bacterial pathogens [
9]. Furthermore, local administration of AKB-4924
in vivo was shown to limit progression of
Staphylococcus aureus skin infection [
9]. AKB-4924 has previously been shown to stabilize HIF-1α, and to a lesser degree HIF-2α, in mouse fibroblasts, demonstrated by up-regulation of known HIF target genes such as vascular endothelial growth factor (VEGF) and glucose transporter-1 [
9]. However, the effects of AKB-4924 on a cellular level in keratinocytes that contribute to the observed innate immune boosting remain unclear. In this focused study, we investigated the effect of the HIF-stabilizing agent AKB-4924 on keratinocytes. Specifically, the production of VEGF, involved in enhancing permeability of the local microvasculature [
10], interleukin-8 (IL-8), a C-X-C family chemokine that is the major neutrophil chemo-attractant in humans [
11] and interleukin-6 (IL-6), a pro-inflammatory cytokine that supports neutrophil antibacterial activity in the skin, and the role that HIF plays in neutrophil recruitment
in vivo[
12].