BACKGROUND/AIMS: The transcription factor NFkappaB is a major mediator of lipopolysaccharide (LPS) signaling. We determined the role of NFkappaB activation in regulatory changes of the P-glycoprotein (Pgp) drug efflux transporter at the blood-brain barrier (BBB) and proinflammatory cytokine receptors. METHODS: We treated NFkappaB knockout and wildtype mice with LPS or vehicle, obtained enriched cerebral microvessels, and determined target mRNA by qPCR for MDR1a/b, IL15Ralpha, IL2 Ralpha, IL2Rgamma, LIFR, gp130, and TNFR1/2, and protein expression by western blotting for P-gp, IL15Ralpha, IL2Rgamma, LIFR, and gp130. RESULTS: The effects of LPS on the transporters and cytokine receptors showed differences between wildtype and NFkappaB knockout mice, and between mRNA and protein changes. NFkappaB not only mediated the LPS-induced increase of MDR1b, IL2Rgamma, and TNFR2 mRNA in the wildtype mice, but it showed opposite effects by elevating IL15Ralpha and TNFR1 mRNA and decreasing IL2Ralpha in the knockout mice. Although basal vinblastine uptake was unchanged in the NFkappaB knockout mice, LPS induced an increase of the uptake (depressed efflux transport) greater than that seen in the wildtype mice, indicating that NFkappaB helps to maintain Pgp efflux transporter function. CONCLUSION: The results show differential involvement of NFkappaB signaling in response to LPS at the BBB. Copyright 2010 S. Karger AG, Basel.
BACKGROUND/AIMS: The transcription factor NFkappaB is a major mediator of lipopolysaccharide (LPS) signaling. We determined the role of NFkappaB activation in regulatory changes of the P-glycoprotein (Pgp) drug efflux transporter at the blood-brain barrier (BBB) and proinflammatory cytokine receptors. METHODS: We treated NFkappaB knockout and wildtype mice with LPS or vehicle, obtained enriched cerebral microvessels, and determined target mRNA by qPCR for MDR1a/b, IL15Ralpha, IL2 Ralpha, IL2Rgamma, LIFR, gp130, and TNFR1/2, and protein expression by western blotting for P-gp, IL15Ralpha, IL2Rgamma, LIFR, and gp130. RESULTS: The effects of LPS on the transporters and cytokine receptors showed differences between wildtype and NFkappaB knockout mice, and between mRNA and protein changes. NFkappaB not only mediated the LPS-induced increase of MDR1b, IL2Rgamma, and TNFR2 mRNA in the wildtype mice, but it showed opposite effects by elevating IL15Ralpha and TNFR1 mRNA and decreasing IL2Ralpha in the knockout mice. Although basal vinblastine uptake was unchanged in the NFkappaB knockout mice, LPS induced an increase of the uptake (depressed efflux transport) greater than that seen in the wildtype mice, indicating that NFkappaB helps to maintain Pgp efflux transporter function. CONCLUSION: The results show differential involvement of NFkappaB signaling in response to LPS at the BBB. Copyright 2010 S. Karger AG, Basel.
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