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

Abstract

Background/aims: The transcription factor NFĸB is a major mediator of lipopolysaccharide (LPS) signaling. We determined the role of NFĸB 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 NFĸB knockout and wildtype mice with LPS or vehicle, obtained enriched cerebral microvessels, and determined target mRNA by qPCR for MDR1a/b, IL15RΑ, IL2 RΑ, IL2RΓ, LIFR, gp130, and TNFR1/2, and protein expression by western blotting for P-gp, IL15RΑ, IL2RΓ, LIFR, and gp130. Results: The effects of LPS on the transporters and cytokine receptors showed differences between wildtype and NFĸB knockout mice, and between mRNA and protein changes. NFĸB not only mediated the LPS-induced increase of MDR1b, IL2RΓ, and TNFR2 mRNA in the wildtype mice, but it showed opposite effects by elevating IL15RΑ and TNFR1 mRNA and decreasing IL2RΑ in the knockout mice. Although basal vinblastine uptake was unchanged in the NFĸB knockout mice, LPS induced an increase of the uptake (depressed efflux transport) greater than that seen in the wildtype mice, indicating that NFĸB helps to maintain Pgp efflux transporter function. Conclusion: The results show differential involvement of NFĸB signaling in response to LPS at the BBB.