Abstract
The IKKβ is known to regulate transcription factor NF-κB activation leading to inflammatory responses. Recent gene knockout studies have shown that IKKβ can orchestrate local inflammatory responses and regulate homeostasis of epithelial tissues. To investigate whether IKKβ has an intrinsic role in epithelial cells, we established an in vivo system in the immune privileged corneal epithelium. We generated triple transgenic Krt12rtTA/rtTAt/tet-O-Cre/IkkβF/F (IkkβΔCE/ΔCE) mice by crossing the Krt12-rtTA knock-in mice, which express the reverse tetracycline transcription activator in corneal epithelial cells, with the tet-O-Cre and IkkβF/F mice. Doxcycline-induced IKKβ ablation occurred in corneal epithelial cells of triple transgenic IkkβΔCE/ΔCE mice, but loss of IKKβ did not cause ocular abnormalities in fetal development and postnatal maintenance. Instead, loss of IKKβ significantly delayed healing of corneal epithelial debridement without affecting cell proliferation, apoptosis or macrophage infiltration. In vitro studies with human corneal epithelial cells (HCEpi) also showed that IKKβ was required for cytokine-induced cell migration and wound closure but was dispensable for cell proliferation. In both in vivo and in vitro settings, IKKβ was required for optimal activation of NF-κB and p38 signaling in corneal epithelial cells, and p38 activation is likely mediated through formation of an IKKβ-p38 protein complex. Thus, our studies in corneal epithelium reveal a previously un-recognized role for IKKβ in the control of epithelial cell motility and wound healing.
Highlights
The IkB kinase (IKK) complex, composed of two kinases (IKKa and IKKb) and a regulatory subunit IKKc, is the critical signaling mediator for classical nuclear factor-kB (NF-kB) activation [1,2]
Using the corneal epithelial debridement model and mice with inducible and cell type-specific Ikkb gene ablation, we have shown that the corneal epithelial IKKb is required for optimal reepithelialization and wound healing
While loss of IKKb does not seem to perturb the injury-induced proliferation, apoptosis and macrophage activation, it significantly reduces the activation of NF-kbB and p38/ATF2 pathways in the corneal epithelial cells adjacent to the injury sites
Summary
The IkB kinase (IKK) complex, composed of two kinases (IKKa and IKKb) and a regulatory subunit IKKc, is the critical signaling mediator for classical NF-kB activation [1,2]. The IKK complex, especially the IKKb subunit, is responsible for catalyzing IkB phosphorylation, leading to a rapid IkBa ubiquitination and degradation This results in the release of the nuclear factor-kB (NF-kB) transcription factor, which in turn translocate to the nucleus, bind to DNA and activate gene transcription. While systematic Ikkb gene deletion in mice leads to embryonic lethality [5,6], conditional Ikkb ablation in specific cell types has largely avoided developmental defects Studies of these mice so far reveal diverse cell type-specific roles of IKKb. In keratinocytes, IKKb acts to maintain the immune homeostasis of the skin [7,8]; in neurons, it inhibits sensory neuron excitability [9]; in hepatocytes, it suppresses cell proliferation [10,11]; and in mammary epithelial cells, IKKb potentiates apoptosis that leads to mammary gland involution [12]
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