RESUMEN
BACKGROUND: The tumor necrosis factor (TNF) superfamily cytokine TNF-like protein 1A (TL1A) and its receptor DR3 are essential for diverse animal models of autoimmune disease and may be pathogenic in rheumatoid arthritis (RA). However, the relationship of TL1A to disease duration, activity, and response to anti-TNF and other therapies in RA is not clear. METHODS: We measured soluble TL1A in synovial fluid (SF), serum, or plasma from RA first-degree relatives (FDRs) and in early RA and established disease. We measured the effects of anti-TNF and methotrexate (MTX) therapy on circulating TL1A from multiple independent RA treatment trials. We also determined the ability of a blocking anti-TL1A antibody to inhibit clinical disease and articular bone destruction in the murine collagen-induced arthritis (CIA) model of human RA. RESULTS: Soluble TL1A was specifically elevated in the blood and SF of patients with RA compared to patients with other diseases and was elevated early in disease and in at-risk anti-cyclic citrullinated peptide (CCP) (+) first-degree relatives (FDRs). Therapeutic TNF inhibition reduced serum TL1A in both responders and non-responders, whereas TL1A declined following MTX treatment only in responders. In murine CIA, TL1A blockade was clinically efficacious and reduced bone erosions. CONCLUSIONS: TL1A is specifically elevated in RA from early in the disease course and in at-risk FDRs. The decline in TL1A after TNF blockade suggests that TL1A levels may be a useful biomarker for TNF activity in RA. These results support the further investigation of the relationship between TL1A and TNF and TL1A blockade as a potential therapeutic strategy in RA.
Asunto(s)
Artritis Experimental , Artritis Reumatoide , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/sangre , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/genética , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/genética , Humanos , Metotrexato/uso terapéutico , Ratones , Líquido Sinovial , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/antagonistas & inhibidores , Factor de Necrosis Tumoral alfaRESUMEN
OBJECTIVE: Chronic inflammation of the arteries is a critical mechanism responsible for coronary atherosclerosis. We aimed to determine if tumor necrosis factor (TNF)-like cytokine 1A (TL1A) and decoy receptor 3 (DcR3) were involved in promoting atherosclerosis. METHODS: We compared plasma levels of TL1A and DcR3 in patients with coronary artery disease (CAD) undergoing coronary artery bypass grafting (n=40) and patients without CAD group (n=37, normal coronary artery angiogram) by enzyme-linked immunosorbent assay. We also analyzed the correlation between CAD and SYNTAX scores. RESULTS: Plasma levels of TL1A and DcR3 were significantly higher in the CAD compared with the no-CAD group. Multivariate analysis showed that TL1A and DcR3 were significantly correlated with the presence of CAD, and receiver operating characteristic curve analysis indicated that both TL1A and DcR3 showed high sensitivity and specificity for diagnosing CAD. Furthermore, TL1A was positively and significantly correlated with SYNTAX score in CAD patients. CONCLUSIONS: CAD patients requiring coronary artery bypass grafting have high circulating levels of both TL1A and DcR3, which may thus be useful biomarkers for diagnosing severe CAD. Furthermore, plasma levels of TL1A correlate with SYNTAX score, supporting its potential use as an indicator of the severity of CAD.
Asunto(s)
Biomarcadores/sangre , Procedimientos Quirúrgicos Cardíacos , Enfermedad de la Arteria Coronaria/sangre , Miembro 6b de Receptores del Factor de Necrosis Tumoral/sangre , Índice de Severidad de la Enfermedad , Miembro 15 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/sangre , Estudios de Casos y Controles , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/patología , Enfermedad de la Arteria Coronaria/cirugía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Factores de RiesgoRESUMEN
In mammals, anorexia accompanying infection is thought to be mediated via cytokines including interleukins, interferons (IFNs), and tumor necrosis factor (TNF). However, there is a lack of related knowledge on birds. Therefore, the purpose of the present study was to determine if cytokines are associated with reduced food intake in chicks (Gallus gallus). Specifically, we evaluated the effects of TNF-like cytokine 1A (TL1A), a member of the TNF family, interferon-α (IFN-α), and interferon-γ (IFN-γ) on food intake. Additionally, the effect of lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (poly I:C) on cytokine mRNA expression in the diencephalon and spleen was also measured. Intracerebroventricular (ICV) injection of 0.05 or 0.5⯵g TL1A, IFN-α, and IFN-γ had no effect on food intake. However, when 1.0⯵g each of these factors was evaluated, TL1A significantly decreased food intake at 180 and 240â¯min after the injection, but IFN-α and IFN-γ had no effect. When chicks received intraperitoneal (IP) injections of 100⯵g LPS or 400⯵g poly I:C, their food intake was reduced. Diencephalic mRNA expression of TL1A was significantly decreased following IP injection of LPS or poly I:C. Additionally, diencephalic mRNA expression of IFN-γ mRNA was significantly increased by IP injection of LPS but decreased by IP injection of poly I:C. For the spleen, IP injection of LPS and poly I:C both significantly increased TL1A and IFN-γ mRNA expression. In sum, we have provided evidence that central TL1A but not IFN-α or IFN-γ are related to reduction of food intake in chicks, but the role of these cytokines for mediating anorexia associated with infections may differ from mammals.