Anti–interleukin‐6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis

Abstract

ObjectiveTo investigate whether interleukin‐6 (IL‐6) is a regulator of vascular endothelial growth factor (VEGF) in rheumatoid arthritis (RA).MethodsSerum VEGF levels in RA patients were assayed before and after 8 weeks or 24 weeks of maintenance therapy with humanized anti–IL‐6 receptor monoclonal antibody (anti–IL‐6R mAb). VEGF secreted by RA synovial fibroblasts cultured in the presence of IL‐6, IL‐1β, and/or tumor necrosis factor α (TNFα) was measured. The inhibitory effect of anti–IL‐6R mAb, recombinant IL‐1 receptor antagonist (IL‐1Ra), and anti‐TNFα mAb on VEGF production was also examined.ResultsSerum VEGF levels in RA patients before anti–IL‐6R mAb therapy were significantly higher than those in healthy controls (P < 0.0005). Treatment of RA patients with anti–IL‐6R mAb normalized serum VEGF levels. In the in vitro study, IL‐6 and IL‐1β each induced a slight amount of VEGF production in synovial cells, but TNFα did not. Although VEGF‐inducing activity of these cytokines was not remarkable when they were added alone, IL‐6 acted synergistically with IL‐1β or TNFα to induce VEGF production. There was no synergistic effect between IL‐1β and TNFα. In the presence of all of these cytokines, anti–IL‐6R mAb eliminated the synergistic effect of IL‐6, IL‐1β, and TNFα, while IL‐1Ra or anti‐TNFα mAb did not.ConclusionAnti–IL‐6R mAb therapy reduced VEGF production in RA. IL‐6 is the pivotal cytokine that induces VEGF production in synergy with IL‐1β or TNFα, and this may be the mechanism by which IL‐6 blockade effectively suppresses VEGF production in synovial fibroblasts.

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“…Since IL-6 has biological activities similar to those of IL-1, such as inducing the production of pyrogenic factors and acute phase proteins, and is elevated in morbid synovial fluid, such as that of patients with rheumatoid arthritis, it initially attracted attention due to its possible relationship with cartilage destruction. In addition, IL-6 is a pre-inflammatory cytokine, and an IL-6 receptor antagonist is being used as an anti-inflammation drug for RA [14,15]. In this study, the IL-6 concentration was high in many knees within 50 weeks after ACL injury but decreased thereafter, while the MMP-3 concentration was elevated regardless of the time after injury.…”

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“…IL-6 up-regulates the production of vascular endothelial growth factor (VEGF), which plays important roles in angiogenesis in synovium. 14) Tocilizumab may exert its anti-inflammatory effect via the inhibition of these IL-6 biological activities.…”

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“…Moreover, IL-6 production in bone marrow stromal cells induces receptor activator of NF-kappaB ligand (RANKL), which is an essential factor for the differentiation and activation of osteoclasts and bone resorption [20], and the increase in osteoclast development is mediated by IL-6 after postmenopausal estrogen loss [21]. Enhanced angiogenesis and increased vascular permeability of synovial tissue are pathological features of RA, and these characteristics are due to the excess production of vascular endothelial growth factor (VEGF), which is induced by IL-6 in synovial fibroblasts [22]. The promotional activities of IL-6 such as the proliferation of keratinocytes or collagen production in dermal fibroblasts may contribute to autoimmune skin diseases such as psoriasis and systemic sclerosis, respectively [23,24].…”