Tsuyoshi Kasama

Clinical Relevance of Cytokines, Chemokines and Adhesion Molecules in Systemic Vasculitis

Although the causes of most vasculitis syndromes remain unclear, advances in molecular and cellular immunology have enabled the definition of many effector mechanisms that mediate inflammatory vascular damage. Vascular endothelial dysfunction is observed in a variety of immune-mediated inflammatory diseases. Therefore, endothelial cells (ECs) play a pivotal role in the pathogenesis of systemic vasculitis (Buckley et al. 2005; Kaneider et al. 2006), in large part by amplifying and perpetuating the inflammatory process through the expression and secretion of various cytokines, chemokines, cell adhesion molecules, and other inflammatory molecules. In addition, specific cell-cell interactions, especially between ECs and invading mononuclear cells, including macrophages and lymphocytes, also contribute to the progression of systemic vasculitis and other autoimmune diseases, including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In addition, recent studies of the pathogenesis of atherosclerosis have shown that a key feature of atherosclerotic disease is the alternating interaction and amplification of thrombosis and inflammation, which is considered an unusual form of chronic inflammation of the artery wall that is triggered by chemical (e.g., smoking and hyperlipidemia), biological (e.g., Chlamydia pneumoniae) and/or mechanical (e.g., shear stress in hypertension) insults to ECs (Libby 2002). Among the various mediators secreted by activated inflammatory cells are cytokines and chemokines, which appear to be involved in both systemic vasculitis and atherosclerosis. The purpose of this review is to provide an overview of the expression and function of the cytokines and chemokines during the pathogenesis of vasculitic diseases, including systemic vasculitis and related conditions.

Cytokine-mediated Regulation of CX3CL1 in Osteoblasts from Patients with Rheumatoid Arthritis

Introduction CX3CL1 (fractalkine), a membrane-bound chemokine that induces both the adhesion and migration of leukocytes, is involved in the recruitment of cells to tissues undergoing inflammatory responses. To explore the regulation of CX3CL1 in inflammatory bone diseases, we examined CX3CL1 expression in osteoblasts. Methods Human osteoblasts isolated from the femora of rheumatoid arthritis patients were incubated in the presence or absence of various inflammatory stimuli. Culture supernatants were collected, and soluble CX3CL1 levels were determined with an enzyme-linked immunosorbent assay (ELISA). The expression of CX3CL1 mRNA transcripts in osteoblasts was examined using the quantitative TaqMan real-time polymerase chain reaction. Results The combination of tumor necrosis factor (TNF)-α and interferon (IFN)-γ induced dramatic increases in levels of both soluble CX3CL1 protein and mRNA transcripts. CX3CL1 expression in osteoblasts was decreased by the addition of interleukin(IL)-4 or IL-17 but was increased when stimulation by IFN-γ and IL-17 was supplemented with IL-1β In addition, expression was decreased when TNF-α was added. Conclusions Multiple cytokines, including IL-17, are able to either increase or decrease the expression of CX3CL1 by human osteoblasts.

Clinical Relevance of Cytokines and Inflammatory Molecules in Rheumatoid Vasculitis

Rheumatoid vasculitis (RV) is an uncommon but severe complication of rheumatoid arthritis (RA) that can cause skin disorders, such as rash, cutaneous ulcerations and gangrene, neuropathy, eye symptoms, and systemic inflammation. Although the molecular mechanisms underlying RV in RA are unclear, it is well known that a chronic imbalance in the expression of chemokines and proinflammatory cytokines is important for orchestrating inflammatory responses in RA patients, and similar dysregulation of cytokines and other inflammatory molecules, such as adhesion molecules, has been suggested to occur in patients with RV. Recently, we reported elevated levels of the soluble form of CX3CL1, which is a newly described membrane-bound CX3C chemokine, in the serum of patients with RV. In the present review, we discuss the involvement of cytokines and inflammatory molecules in the pathogenesis of RV and evaluate their significance as useful laboratory parameters of active vasculitis disease.

Expression and Function of Cytokines and Chemokines in Neuropsychiatric Related Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multi-organ damage, and the neuropsychiatric complications of SLE (NPSLE) are associated with increased morbidity and mortality. In general, the diagnosis of NPSLE is difficult, because no single laboratory marker or imaging modality has been found which can serve as a gold standard, and the diagnosis is thus primarily clinical. The pathogenesis of NPSLE has not been fully elucidated. Focal symptoms are thought to more likely result from vascular lesions, whereas diffuse manifestations are more likely related to autoantibody- or cytokine-mediated impairment of neuronal function. However recent progress has provided evidence that a number of cytokines and chemokines, as well as autoantibodies, may be involved in the neuropsychiatric manifestations of SLE, because certain repertoires of cytokines/chemokines are detectable in the central nervous system of NPSLE patients during active disease. In addition, we have recently shown elevated levels of the soluble form of fractalkine, which is a newly described membrane-bound CX3C chemokine, in the cerebrospinal fluid of patients with active NPSLE. This review will discuss the involvement of cytokines and chemokines in the pathogenesis of NPSLE and the evaluation of their significance as a useful laboratory parameter of active neuropsychiatric disease.