Impact of interleukin‐6 on drug transporters and permeability in the hCMEC/D3 blood–brain barrier model

Abstract

The blood–brain barrier (BBB) is a highly selective membrane composed predominantly of brain capillary endothelial cells expressing drug efflux transporters that prevent substrates from accessing the brain. Inflammation is associated with central nervous system diseases and can impair BBB permeability via several mechanisms, including altered transporter and cell junction expression. This can modify the brain’s exposure to drugs. However, comprehensive genomic analysis of the impact of interleukin (IL)‐6, which plays a key role in the inflammatory response, on the BBB is lacking. In the present study, we analyzed the effects of exposure of hCMEC/D3 cells to 20 ng/mL IL‐6 for 72 h. We performed RNA sequencing and ABC transporter efflux assays. Physiologically based pharmacokinetics (PBPK) simulations were conducted to evaluate the potential impact of IL‐6 on the digoxin pharmacokinetics profile and brain exposure by decreasing BBB ABCB1 efflux activity. Exposure of hCMEC/D3 cells to IL‐6 triggered the deregulation of numerous genes involved in barrier permeability, such as cell junctions, focal adherens complex, and cell adhesion molecules. We observed mild modification of the mRNA expression and efflux activities of ABC transporters. PBPK simulation showed that, if we only consider the impact of IL‐6 on ABCB1 transporter, the modification of the digoxin pharmacokinetics profile and brain exposure is slight. IL‐6 slightly affected the gene expression levels and activities of ABC transporters on BBB cells, exhibiting a weaker effect than on hepatic cells. However, inflammation may cause other modifications, such as altered BBB permeability, that could modify drug pharmacokinetics.

Assessment of the drug–drug interaction potential for therapeutic proteins with pro‐inflammatory activities

“…In the human brain endothelial cell line hCMEC/D3 cell line, in vitro model of the human blood–brain barrier (BBB), IL‐6 treatment slightly decreased the P‐gp mRNA level by 21% and had no significant impact on protein expression, and transporter activity 25 . Similar findings were observed in another study, IL‐6 treatment with hCMEC/D3 cell line reduced the P‐gp mRNA level by 43%, but only had mild modification of P‐gp transporter activity 26 …”

“…reduced the P-gp mRNA level by 43%, but only had mild modification of P-gp transporter activity. 26 IFN-γ IFN-γ is a dimerized cytokine, secreted primarily by T helper cell type 1 (Th1) cells, CD8+ T cells, B cells, NK cells, and antigen presenting cells (monocytes, macrophages, and dendritic cells). 27 The monomer has a molecular weight of 20-25 kDa, and it is composed of a core of six-αhelix-bundle and an extended C-terminal region.…”

In Vitro Methodologies to Study the Role of Advanced Glycation End Products (AGEs) in Neurodegeneration

“…The human hCMEC/D3 cell line is derived from primary microvessel endothelial cells immortalised with SV40 and hTERT lentiviral transduction [228]. Due to its human origin, this cell line is widely used to study transporters and receptors for drug delivery to the brain [229][230][231][232]. An extensive characterisation of this cell line showed that the cells express endothelial and BBB markers and have a highly restricted permeability to molecules, which is closer to the physiological frame than animal immortalised brain endothelial cells [228].…”

Inflammation Induces Changes in the Functional Expression of P-gp, BCRP, and MRP2: An Overview of Different Models and Consequences for Drug Disposition

“…In addition, it is known that CYP3A and P-gp are both regulated by the same nuclear receptor, PXR [ 154 , 155 ]. Thus, it would be interesting to integrate all the pharmacokinetic actors in physiologically-based pharmacokinetic modeling (PBPK) to establish more complete in vitro–in vivo correlations, as suggested by Simon et al (2020) [ 156 ]. Conducting prospective and retrospective studies in humans could provide more evidence, by establishing for example, a link between the level of inflammatory markers such as CRP and a modulation of drug exposure [ 130 , 138 ].…”