The exaggerated inflammatory response in Behçet's syndrome: identification of dysfunctional post-transcriptional regulation of the IFN-γ/CXCL10 IP-10 pathway

Abstract

SummaryThe mechanisms underlying the exaggerated inflammatory response in Behc¸et's syndrome (BS) remain poorly understood. We investigated the response of CD14 1 blood monocytes to interferon (IFN)-g, focusing on the chemokine CXCL10. Chemokine synthesis and release were analysed at a protein and mRNA level following stimulation with IFN-g. Findings in BS patients were compared with 25 healthy controls (HC), 15 rheumatoid arthritis (RA) and 15 systemic lupus erythematosus (SLE) disease control patients. BS monocytes produced significantly more CXCL10 protein than HC monocytes from 2 h following IFN-g stimulation, despite equivalent quantities of mRNA, suggesting more efficient translation. This was significantly more pronounced in BS with high disease activity and in those with ocular and neurological clinical manifestations. The imbalance between CXCL10 protein and mRNA expression was not observed in either RA or SLE patients, and was not seen with other chemokines studied (CXCL9, CXCL11 and CCL2). Furthermore, BS monocytes treated with an alternative stimulant (LPS) did not show abnormal tumour necrosis factor (TNF)-a release. Sucrose density gradients to segregate monocyte CXCL10 mRNA into free RNA or polysome-associated RNA showed equal proportions in BS and HC samples, suggesting that the difference between BS and HC may be due to reduced negative control of CXCL10 translation in BS at a postinitiation level. We conclude that BS monocytes have dysfunctional posttranscriptional regulation of CXCL10 mRNA, resulting in over-expression of CXCL10 protein upon IFN-g stimulation. As CXCL10 is a chemokine that recruits mononuclear cells, this abnormality may contribute to the exaggerated inflammatory responses that characterizes BS.

Longitudinal IP-10 Serum Levels Are Associated with the Course of Disease Activity and Remission in Patients with Rheumatoid Arthritis

“…The increase in IP-10 serum levels during acute inflammatory episodes of leprosy (7)(8)(9), the exaggerated inflammatory responses in Behçet's syndrome (32), and the association with augmented RA disease activity observed in this study suggest a longitudinal increase in IP-10 as a general marker for episodes of exacerbated inflammation. The association of IP-10 with DAS shows that rapid assessment of IP-10 levels by use of user-friendly UCP-LFAs can potentially be used as an easy and cheap alternative or additional tool to help monitor disease activity in RA.…”

Cytokine and chemokine tear levels in patients with uveitis

“…IP‐10/CXCL10 has also been involved in the pathogenesis of ocular Behcet's disease (Ambrose et al. ).…”

The CXCL10/CXCR3 Axis and Cardiac Inflammation: Implications for Immunotherapy to Treat Infectious and Noninfectious Diseases of the Heart

“…The basis for the pathogenesis of Behçet's disease is not known, although a number of factors have been proposed to have a role, including viral, bacterial, environmental, genetic, and immune factors. Behçet's is caused by small-vessel systemic vasculitis that very often affects the heart in diverse ways, including endomyocardial fibrosis, intracardiac thrombus, endocarditis, pericarditis, myocarditis, coronary arteritis, myocardial infarction, and valvular disease [ 70 ]. The cardiomyopathy may be ischemic, nonischemic, or inflammatory in nature and may manifest as asymptomatic systolic or diastolic dysfunction or overt systolic or diastolic heart failure [ 70 ].…”

“…Behçet's is caused by small-vessel systemic vasculitis that very often affects the heart in diverse ways, including endomyocardial fibrosis, intracardiac thrombus, endocarditis, pericarditis, myocarditis, coronary arteritis, myocardial infarction, and valvular disease [ 70 ]. The cardiomyopathy may be ischemic, nonischemic, or inflammatory in nature and may manifest as asymptomatic systolic or diastolic dysfunction or overt systolic or diastolic heart failure [ 70 ]. Recently, monocytes of Behçet's patients were found to have dysfunctional posttranscriptional regulation of CXCL10 mRNA that resulted in overexpression of CXCL10 protein with IFN- γ stimulation [ 70 ].…”

“…The cardiomyopathy may be ischemic, nonischemic, or inflammatory in nature and may manifest as asymptomatic systolic or diastolic dysfunction or overt systolic or diastolic heart failure [ 70 ]. Recently, monocytes of Behçet's patients were found to have dysfunctional posttranscriptional regulation of CXCL10 mRNA that resulted in overexpression of CXCL10 protein with IFN- γ stimulation [ 70 ]. Thus, overexpression of CXCL10 may contribute to the pathogenesis of Behçet's disease.…”