RESUMEN
IL-6 is a multifunctional proinflammatory cytokine that is elevated in the serum of patients with pulmonary arterial hypertension (PAH) and can predict the survival of patients with idiopathic PAH (IPAH). Previous animal experiments and clinical human studies indicate that IL-6 is important in PAH; however, the molecular mechanisms of IL-6-mediated pathogenesis of PAH have been elusive. Here we identified IL-21 as a downstream target of IL-6 signaling in PAH. First, we found that IL-6 blockade by the monoclonal anti-IL-6 receptor antibody, MR16-1, ameliorated hypoxia-induced pulmonary hypertension (HPH) and prevented the hypoxia-induced accumulation of Th17 cells and M2 macrophages in the lungs. Consistently, the expression levels of IL-17 and IL-21 genes, one of the signature genes for Th17 cells, were significantly up-regulated after hypoxia exposure in the lungs of mice treated with control antibody but not in the lungs of mice treated with MR16-1. Although IL-17 blockade with an anti-IL-17A neutralizing antibody had no effect on HPH, IL-21 receptor-deficient mice were resistant to HPH and exhibited no significant accumulation of M2 macrophages in the lungs. In accordance with these findings, IL-21 promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Of note, significantly enhanced expressions of IL-21 and M2 macrophage markers were detected in the lungs of IPAH patients who underwent lung transplantation. Collectively, these findings suggest that IL-21 promotes PAH in association with M2 macrophage polarization, downstream of IL-6-signaling. The IL-6/IL-21-signaling axis may be a potential target for treating PAH.
Asunto(s)
Hipertensión Pulmonar/fisiopatología , Interleucina-6/metabolismo , Interleucinas/metabolismo , Transducción de Señal/fisiología , Remodelación Vascular/fisiología , Análisis de Varianza , Animales , Anticuerpos Monoclonales/inmunología , Presión Sanguínea , Western Blotting , Pesos y Medidas Corporales , Cartilla de ADN/genética , Citometría de Flujo , Humanos , Inmunohistoquímica , Interleucina-6/sangre , Macrófagos/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Interleucina-21/deficienciaRESUMEN
Treatment of refractory Takayasu arteritis (TA) remains an unresolved clinical issue. Patients usually respond to glucocorticoid (GC) therapy, but often relapse on tapering of the GC dose. The aim of the present study was to assess the safety and efficacy of the interleukin-6 (IL-6) receptor antibody tocilizumab (TCZ) in patients with TA refractory to conventional therapies including GC. Four patients with TA who had shown GC resistance received TCZ infusions (8 mg/kg) every 4 weeks a total of at least 24 times (range, 24 to 51). Clinical symptoms, the serum levels of acute phase proteins and IL-6, GC dosage necessary to maintain remission, and cross-sectional imaging by enhanced CT and MRI were assessed. All patients achieved good clinical response and rapid normalization of the acute phase proteins such as C-reactive protein and serum amyloid A during the therapy with TCZ. The mean dosage of prednisolone could be reduced from 21.3 mg/day to 1.5 mg/day. Although the serum IL-6 level was transiently elevated in all patients after several TCZ infusions, it gradually recovered to the initial level. Along with the decrease of serum IL-6, two patients exhibited significant reduction in thickened arterial lesions. No drug-related adverse effects were noted. In this small group of patients with refractory TA, TCZ therapy was effective and well-tolerated. Further larger studies should be conducted to confirm this finding.