Associations between Cytokine Levels and CYP3A4 Phenotype in Patients with Rheumatoid Arthritis

Abstract

Systemic inflammation has been linked to suppressed CYP3A4 activity. The aim of this study was to examine associations between levels of a broad selection of cytokines and CYP3A4 phenotype in patients with rheumatoid arthritis (RA). The study included 31 RA patients treated with tumor necrosis factor (TNF)-α inhibitors. CYP3A4 phenotype was measured as serum concentration of 4β-hydroxycholesterol (4βOHC) by ultra-performance liquid chromatography-tandem mass spectrometry in samples collected prior to and 3 months after initiation of treatment with TNF-α inhibitors. Serum levels of the following 21 cytokines were determined in the same samples using a bead-based multiplex immunoassay (Luminex technology): CCL2, CCL3, CXCL8, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, interferon γ, interleukin (IL)-1β, IL-1 receptor antagonist (ra), IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL-13, IL-15, IL-17A, IL-18, IL-23, and TNF-α Correlations between levels of cytokines and 4βOHC were assessed by Spearman's rank correlation tests. Among the investigated cytokines, three were negatively correlated with CYP3A4 phenotype during treatment with TNF-α inhibitors: i.e., IL-1ra (r = -0.408, P = 0.023), IL-6 (r = -0.410, P = 0.022) and CXCL8 (r = -0.403, P = 0.025) (P ≥ 0.3 for all other cytokines). None of the analyzed cytokines were correlated with CYP3A4 phenotype prior to TNF-α inhibitor treatment (P > 0.1 for all cytokines). These findings suggest that immune responses associated with increased levels of IL-1ra, IL-6, and CXCL8 may suppress CYP3A4 metabolism. Further studies are required to evaluate these preliminary findings in different patient populations and also examine the possible molecular mechanisms behind our observations.