Immunodepletion of candidate chemokines, cytokines, and growth factors demonstrate selective dependence of HIF-1α–mediated inflammatory hyper-responsiveness on NFκB targets. Transgenic mice were pretreated with neutralizing antibodies targeting either KC (A), a KC/MIP-2 cocktail (B), TNFα (C), or a VEGFR1/VEGFR2 cocktail (D). Twenty-four hours later, a single dose of TPA (2.5 μg) was applied to the ear followed by tissue harvest 6 hours later and hematoxylin and eosin histostaining. Immunodepletion with either KC or TNFα antibodies markedly decreased, whereas the KC/MIP-2 cocktail abrogated, HIF-1α–mediated inflammatory hyper-responsiveness. In marked contrast, transgenic ears were resistant to VEGFR1/VEGFR2 immunodepletion. Immunofluorescence for GR1 expression confirms that KC/MIP-2 depletion abrogates neutrophil recruitment to TPA-challenged transgenic ears (E, GR1, green; K14, red). In contrast, immunodepleted, TPA-challenged transgenic ears retain elevated subepidermal microvascular density and lymphatic dilatation (F, MECA32, green; LYVE-1, red). Decreased immunofluorescence for ICAM1 on TPA-challenged transgenic ears pretreated with VEGFR1/2 neutralizing antibodies (H, ICAM-1, green; MECA32, red) versus nonpretreated and TPA-challenged transgenic ears (G, ICAM-1, green; MECA32, red) confirms the effectiveness of VEGFR1/2 antibody treatment. Bar in panel A represents 100 μm.