Inflammatory Cytokines in the Pathogenesis of Pulmonary Arterial Hypertension

Interleukin-6 (IL-6) is a multifunctional pro-inflammatory cytokine elevated in the serum of pulmonary arterial hypertension (PAH) patients and can predict the survival of idiopathic (I)PAH patients. Previous animal experiments and clinical human studies indicate that IL-6 is important in the pathogenesis of PAH; however, the molecular mechanisms of IL-6-mediated pathogenesis of PAH have been elusive. We recently identified IL-21 as a novel downstream cytokine 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. Furthermore, the hypoxia-induced upregulation of IL-17 and IL-21, which are primarily produced by Th17 cells, was also ameliorated by IL-6 blockade in mice. Whereas IL-17 blockade with an anti-IL-17 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. Consistently, IL-21 indeed promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Moreover, significantly enhanced expressions of IL-21 and M2 macrophage markers were detected in the lungs of IPAH patients who underwent lung transplantation. Together, the above data suggest that IL-21 promotes PAH through M2 macrophage polarization, downstream of IL-6-signaling. IL-6/Th17/IL-21-signaling axis might be a novel potential target for treating PAH.