engleski

Interplay of cytokines and SOCS molecules influence ABC transporter expression in ulcerative colitis

Background: Intact mucosal barrier is of pivotal importance for gut homeostasis as in patients with inflammatory bowel disease (IBD) where commensal bacteria are mistakenly recognized as pathogenic and cause permanent inflammation. Standard therapy regimens aim to eliminate inflammation by restoring cytokine balance. One of the contributing factors are ABC transporters (ATP binding cassette transporters), namely Pgp (P-glycoprotein), MRP1 (multidrug resistance associated protein 1) and BCRP (breast cancer resistance protein) which act as gatekeepers of the gut homeostasis. Disbalance in proinflammatory vs inflammatory status of epithelial lining could be related to aberrant transporter expression and augmented cytokine/chemokines responsible for leukocyte influx. As therapy tends to regulate cytokine production, failure could be a result of altered transporter expression or suppressor of cytokine signalling (SOCS). The aim of this study was to asses mRNA expression profiles of ABC transporters, cytokines and SOCS molecules at ulcerative colitis (UC) patients at distinct regions of colon, as this could help to further illuminate mechanisms contributing to pathogenesis of IBD. Methods: 21 ulcerative colitis (UC) patients were divided into three groups based on the disease status: newly diagnosed (N), active disease (A) and remission (R). The mRNA expression levels of Pgp, MRP1 and BCRP were monitored at six different locations (terminal ileum, ascending, transverse, descending, sigmoid colon and rectum) whereas cytokine (IFN-γ, IL-2, IL-6, IL-1β and IL-17) and SOCS (SOCS-1 and SOCS-3) levels were determined at terminal ileum. 10 healthy patients were included as controls (C). mRNA levels were determined using quantitative real time PCR with GAPDH as endogenous control. Results: Constitutive expression of ABC transporters along human colon is significantly down-regulated in IBD compared to healthy subjects. The mRNA expression of Pgp and BCRP show regional differences with highest expression at terminal ileum whereas MRP1 expression pattern didn’t differ significantly between examined locations. The expression of transporters along colon was as follows: BRCP> Pgp> MRP1. Clinically successful treatment reduced mRNA levels of Pgp and BCRP at terminal ileum and sigma. Levels of IFN-γ, IL-6, IL-1β and IL-17 expression are higher in UC patients than in controls, with IL-6 and IL-1β showing highest expression in active disease. Contrary, IL-2 expression levels were lower compared to controls. Active disease was associated with higher IL-6 levels and lower Pgp and BCRP expression. Remission is characterized with normalized IL-1b, IL-6 and higher IL-2 expression. Levels of SOCS-1 and SOCS-3 were higher in UC patients than controls independent of disease phase. Statistical analysis confirmed positive correlation between proinflammatory cytokine (IL-6 and IL-1β) levels with negative regulators (SOCS-1 and SOCS-3). Conclusion: The expression of Pgp and BCRP is suppressed in the active phase of UC which could have potential implications for drug therapy. Observed BCRP down-regulation, with increased IL-6 and IL-1 β expression, in UC patients is clearly the result of an ongoing chronic inflammation since mRNA levels did not differ between remission group and controls. High SOCS levels, although responsible for negative regulation of cytokine response, could potentially present a threat since high SOCS-3 expressions in remission are correlated with shorter time to relapse.

ABC transporters ; cytokines ; SOCS molecules ; Ulcerative colitis

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