Mechanism of the Regulation of Organic Cation/Carnitine Transporter 1 (SLC22A4) by Rheumatoid Arthritis-Associated Transcriptional Factor RUNX1 and Inflammatory Cytokines

Abstract

ABSTRACT:Recently, it was reported that the organic cation/carnitine transporter 1 (OCTN1, SLC22A4) is associated with chronic inflammatory diseases, such as rheumatoid arthritis (RA) and Crohn's disease. OCTN1 in humans is expressed in synovial tissues of individuals with rheumatoid arthritis. Furthermore octn1 in mice is expressed in inflamed joints with collagen-induced arthritis, a model of human arthritis, but not in the joints of normal mice. OCTN1 should be involved in the inflammatory disease and in the present study, the regulatory mechanism of OCTN1 expression was characterized using the human fibroblast-like synoviocyte cell line MH7A, derived from RA patients. A luciferase-reporter gene assay and gel shift assay demonstrated that RUNX1, which is an essential hematopoietic transcription factor associated with acute myeloid leukemia and is related to RA and Sp1, is involved in the regulation of OCTN1 promoter activity. Inflammatory cytokines such as interleukin-1␤ and tumor necrosis factor-␣ increased the expression of OCTN1 mRNA. Furthermore, overexpression of nuclear factor-B (NF-B) activated promoter activity of OCTN1. These results clearly demonstrate that expression of OCTN1 is regulated by various factors, including RUNX1, inflammatory cytokines, and NF-B, all of which are also related to the pathogenesis of RA. Further studies on the physiological substrate(s) of OCTN1 should be done to clarify the roles of OCTN1 in these diseases.

Functional Genetic Variation in the Basal Promoter of the Organic Cation/Carnitine Transporters OCTN1 (SLC22A4) and OCTN2 (SLC22A5)

“…In addition, an SNP in intron 1 of the gene affects the expression level of OCTN1 by decreasing the binding affinity for RUNX1, which is an essential hematopoietic transcription factor (Tokuhiro et al, 2003). A RUNX1 binding site is also located in the proximal promoter region of the OCTN1 gene but is not essential for promoter activity (Maeda et al, 2007). We did not identify any SNPs in the RUNX1 binding sites of the OCTN1 proximal promoter region among the four ethnic groups (Fig.…”

“…Future studies of the influence of the Ϫ207GϾC on other phenotypes that may be tissue specific, such as the disposition and response to various drugs including ␤-lactam antibiotics and cardiovascular drugs, may be fruitful (Ganapathy et al, 2000;Iwata et al, 2008;Ohnishi et al, 2008). Maeda et al (2007). There were no SNPs in these binding sites of the OCTN1 promoter.…”

Functional Characterization of Ergothioneine Transport by Rat Organic Cation/Carnitine Transporter Octn1 (slc22a4)

“…12) In addition, reactive oxidant species (ROS), such as hydrogen peroxide, underwent an activation of NF-kB. 23) On the other hand, ergothioneine had an inhibitory effect on ROS or TNF-a induced NF-kB activation.…”

“…10,11) On the other hand, we recently found an increase of human OCTN1-mRNA expression by inflammatory cytokine via nuclear factor-kB (NFkB) activation. 12) Moreover, ergothioneine was found to be a good substrate of human OCTN1, 13) and ergothioneine exhibited stimulatory effects on proliferation of human OCTN1-overexpressing Caco-2 cells that are derived from human colonic carcinoma. 14) In addition, some cases of RA patient are associated with a high level of ergothioneine in red blood cells.…”

Localization of Xenobiotic Transporter OCTN1/SLC22A4 in Hepatic Stellate Cells and Its Protective Role in Liver Fibrosis

“…Gene expression of SLC22A4 is induced by treatment with TNF-α, but not other inflammatory cytokines such as interleukin (IL)-1β, 6 and interferon-γ in human intestinal epithelial cells Caco-2 [30], whereas both TNF-α and IL-1β induce SLC22A4 gene expression in human fibroblast-like synoviocyte cell line MH7A [31]. In the present study using LI90, both OCTN1 mRNA and [ 3 H]ERGO uptake were significantly increased by TNF-α, but not TGF-β (Fig.…”