The Role of Cerebral Vascular NF kappa B in LPS-induced Inflammation: Differential Regulation of Efflux Transporter and Transporting Cytokine Receptors

Background/aims: The transcription factor NF kappa B is a major mediator of lipopolysaccharide (LPS) signaling. We determined the role of NF kappa B 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 NF kappa B knockout and wildtype mice with LPS or vehicle, obtained enriched cerebral microvessels, and determined target mRNA by qPCR for MDR1a/b, IL15R alpha, IL2 R alpha, IL2R gamma, LIFR, gp130, and TNFR1/2, and protein expression by western blotting for P-gp, IL15R alpha, IL2R gamma, LIFR, and gp130. Results: The effects of LPS on the transporters and cytokine receptors showed differences between wildtype and NF kappa B knockout mice, and between mRNA and protein changes. NF kappa B not only mediated the LPS-induced increase of MDR1b, IL2R gamma, and TNFR2 mRNA in the wildtype mice, but it showed opposite effects by elevating IL15R alpha and TNFR1 mRNA and decreasing IL2R alpha in the knockout mice. Although basal vinblastine uptake was unchanged in the NF kappa B knockout mice, LPS induced an increase of the uptake ( depressed efflux transport) greater than that seen in the wildtype mice, indicating that NF kappa B helps to maintain Pgp efflux transporter function. Conclusion: The results show differential involvement of NF kappa B signaling in response to LPS at the BBB. Copyright (C) 2010 S. Karger AG, Basel