The IKKalpha and IKKbeta catalytic subunits of IkappaB kinase (IKK) share 51% amino-acid identity and similar biochemical activities: they both phosphorylate IkappaB proteins at serines that trigger their degradation. IKKalpha and IKKbeta differ, however, in their physiological functions. IKKbeta and the IKKgamma/NEMO regulatory subunit are required for activating NF-kappaB by pro-inflammatory stimuli and preventing apoptosis induced by tumour necrosis factor-alpha (refs 5,6,7,8,9,10,11). IKKalpha is dispensable for these functions, but is essential for developing the epidermis and its derivatives. The mammalian epidermis is composed of the basal, spinous, granular and cornified layers. Only basal keratinocytes can proliferate and give rise to differentiated derivatives, which on full maturation undergo enucleation to generate the cornified layer. Curiously, keratinocyte-specific inhibition of NF-kappaB, as in Ikkalpha-/- mice, results in epidermal thickening but does not block terminal differentiation. It has been proposed that the epidermal defect in Ikkalpha-/- mice may be due to the failed activation of NF-kappaB. Here we show that the unique function of IKKalpha in control of keratinocyte differentiation is not exerted through its IkappaB kinase activity or through NF-kappaB. Instead, IKKalpha controls production of a soluble factor that induces keratinocyte differentiation.

Activation of microglia commonly occurs in response to a wide variety of pathological stimuli including trauma, axotomy, ischemia, and degeneration in the CNS. In the retina, prolonged or high-intensity exposure to visible light leads to photoreceptor cell apoptosis. In such a light-reared retina, we found that activated microglia invade the degenerating photoreceptor layer and alter expression of neurotrophic factors such as nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), and glial cell line-derived neurotrophic factor (GDNF). Because these neurotrophic factors modulate secondary trophic factor expression in Müller glial cells, microglia-Müller glia cell interaction may contribute to protection of photoreceptors or increase photoreceptor apoptosis. In the present study, we demonstrate the possibility that such functional glia-glia interactions constitute the key mechanism by which microglia-derived NGF, brain-derived neurotrophic factor (BDNF), and CNTF indirectly influence photoreceptor survival, although the receptors for these neurotrophic factors are absent from photoreceptors, by modulating basic fibroblast growth factor (bFGF) and GDNF production and release from Müller glia. These observations suggest that microglia regulate the microglia-Müller glia-photoreceptor network that serves as a trophic factor-controlling system during retinal degeneration.

Prolonged or high-intensity exposure to visible light leads to photoreceptor cell death. In this study, we demonstrate a novel pathway of light-induced photoreceptor apoptosis involving the low-affinity neurotrophin receptor p75 (p75NTR). Retinal degeneration upregulated both p75NTR and the high-affinity neurotrophin receptor TrkC in different parts of Müller glial cells. Exogenous neurotrophin-3 (NT-3) increased, but nerve growth factor (NGF) decreased basic fibroblast growth factor (bFGF) production in Müller cells, which can directly rescue photoreceptor apoptosis. Blockade of p75NTR prevented bFGF reduction and resulted in both structural and functional photoreceptor survival in vivo. Furthermore, the absence of p75NTR significantly prevented light-induced photoreceptor apoptosis. These observations implicate glial cells in the determination of neural cell survival, and suggest functional glial-neuronal cell interactions as new therapeutic targets for neurodegeneration.

This study evaluated the shear bond strength between dual‐cured resin luting cement and pure zirconium (99.9%) and industrially manufactured yttrium‐oxide‐partially‐stabilized zirconia ceramic, and the effect of MDP (10‐methacryloyloxydecyl dihydrogen phosphate) primer (MP) and zirconate coupler (ZC) on bond strength. Two different‐shaped pure zirconium and zirconia ceramic specimens were untreated or treated with various primers, including different concentrations of MP containing phosphoric acid ester monomer (MDP) in ethanol, ZC containing a zirconate coupling agent in ethanol, or a mixture of MP and ZC. The specimens were then cemented together with dual‐cured resin luting cement (Clapearl DC). Half of the specimens were stored in water at 37°C for 24 h and the other half were thermocycled 10,000 times before shear bond strength testing. The bond strengths of resin luting cement to both the zirconium and zirconia ceramic were enhanced by the application of most MPs, ZCs, and the mixtures of MP and ZC. For the group (MP2.0+ZC1.0) containing 2.0 wt % MP and 1.0 wt % ZC, no significant difference was observed between in shear bond strength before and after thermal cycling for both zirconium and zirconia ceramic (p > 0.05). For the other primers, statistically significant differences in shear bond strength before and after thermal cycling were observed (p < 0.05). The application of the mixture of MP and ZC (MP2.0+ZC1.0) was effective for bonding between zirconia ceramic and dual‐cured resin luting cement. This primer may be clinically useful as an adhesive primer for zirconia ceramic restoration. © 2005 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2006