Association of reduced heme oxygenase-1 with excessive Toll-like receptor 4 expression in peripheral blood mononuclear cells in Behçet's disease

Yohei Kirino,Yoshiaki Ishigatsubo,Atsuhisa Ueda,Reikou Watanabe,Shuji Murakami,Masayoshi Kobayashi,Mitsuhiro Takeno,Atsushi Ihata,Shigeru Ohno,Haruko Ideguchi,Nobuhisa Mizuki

doi:10.1186/ar2367

Abstract

IntroductionToll-like receptors (TLRs) mediate signaling that triggers activation of the innate immune system, whereas heme oxygenase (HO)-1 (an inducible heme-degrading enzyme that is induced by various stresses) suppresses inflammatory responses. We investigated the interaction between TLR and HO-1 in an inflammatory disorder, namely Behçet's disease.MethodsThirty-three patients with Behçet's disease and 30 healthy control individuals were included in the study. Expression levels of HO-1, TLR2 and TLR4 mRNA were semiquantitatively analyzed using a real-time PCR technique, and HO-1 protein level was determined by immunoblotting in peripheral blood mononuclear cells (PBMCs) and polymorphonuclear leukocytes. In some experiments, cells were stimulated with lipopolysaccharide or heat shock protein-60; these proteins are known to be ligands for TLR2 and 4.ResultsLevels of expression of HO-1 mRNA were significantly reduced in PBMCs from patients with active Behçet's disease, whereas those of TLR4, but not TLR2, were increased in PBMCs, regardless of disease activity. Moreover, HO-1 expression in PBMCs from patients with Behçet's disease was repressed in the presence of either lipopolysaccharide or heat shock protein-60.ConclusionThe results suggest that upregulated TLR4 is associated with HO-1 reduction in PBMCs from patients with Behçet's disease, leading to augmented inflammatory responses.

Highlights

Toll-like receptors (TLRs) mediate signaling that triggers activation of the innate immune system, whereas heme oxygenase (HO)-1 suppresses inflammatory responses
Levels of expression of HO-1 mRNA were significantly reduced in peripheral blood mononuclear cells (PBMCs) from patients with active Behçet's disease, whereas those of TLR4, but not TLR2, were increased in PBMCs, regardless of disease activity
The results suggest that upregulated TLR4 is associated with HO-1 reduction in PBMCs from patients with Behçet's disease, leading to augmented inflammatory responses

Summary

Introduction

Toll-like receptors (TLRs) mediate signaling that triggers activation of the innate immune system, whereas heme oxygenase (HO)-1 (an inducible heme-degrading enzyme that is induced by various stresses) suppresses inflammatory responses. We investigated the interaction between TLR and HO-1 in an inflammatory disorder, namely Behçet's disease. Behçet's disease (BD) is an inflammatory disorder of unknown cause, characterized by recurrent oral aphthous ulcers, genital ulcers, uveitis, and skin lesions [1]. Several reports have suggested that ubiquitous antigens presented by micro-organisms, such as heat shock proteins (HSPs), trigger crossreactive autoimmune responses through molecular mimicry machinery, which results in BD [6]. Not just acquired and innate immune systems are activated in BD, because hyperfunction of neutrophils is a hallmark of the disease [7]. Toll-like receptors (TLRs), which are expressed on phagocytes and other cells, recognize

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Conclusion