Etanercept reduces the serum levels of macrophage chemotactic protein-1 in patients with rheumatoid arthritis

Kageyama, Yasunori; Kobayashi, H; Kato, Norihiko; Shimazu, Masahiro

doi:10.1007/s10165-009-0175-z

Cited by 12 publications

(5 citation statements)

References 43 publications

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“…The migration capacity of 1,25(OH) 2 D 3 -treated memory CCR6+ Th cells toward RA synovial fluid was unaffected or partially reduced, in a patient-dependent manner. The differences between patients observed in our study could be treatment-related, since for example CCL2 is inhibited by TNFα treatment (47, 48), and CXCL9 and CXCL10 decrease during treatment response (49). Furthermore, the synovial fluid and memory CCR6+ Th cells were isolated from allogeneic donors, which may play a role in our chemotaxis assays.…”

Section: Discussionmentioning

confidence: 73%

Human Memory Th17 Cell Populations Change Into Anti-inflammatory Cells With Regulatory Capacity Upon Exposure to Active Vitamin D

et al. 2019

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Autoimmune diseases are characterized by an aberrantly activated immune system, resulting in tissue damage and functional disability in patients. An important therapeutic goal is to restore the deregulated immunological balance between pro- and anti-inflammatory T cells. This imbalance is illustrated by elevated levels and activity of memory Th17 cell populations, such as Th17, Th1/Th17, and Th17.1 cells, in various autoimmune diseases. These cells are characterized by the chemokine receptor CCR6, RORC expression and production of IL-17A, IFNγ, and TNFα. Using rheumatoid arthritis (RA) as a model of autoimmune disease, we here demonstrate that pro-inflammatory memory CCR6+ Th cells can switch into anti-inflammatory cells with regulatory capacity using the active vitamin D metabolite 1,25(OH) 2 D 3 . Memory CCR6+ Th cells, excluding Tregs, were sorted from healthy controls or treatment-naïve patients with early rheumatoid arthritis (RA) and cultured with or without 1,25(OH) 2 D 3 . Treatment with 1,25(OH) 2 D 3 inhibited pro-inflammatory cytokines such as IL-17A, IL-17F, IL-22 and IFNγ in memory CCR6+ Th cells from both healthy controls and RA patients. This was accompanied by induction of anti-inflammatory factors, including IL-10 and CTLA4. Interestingly, these formerly pathogenic cells suppressed proliferation of autologous CD3+ T cells similar to classical Tregs. Importantly, the modulated memory cells still migrated toward inflammatory milieus in vitro , modeled by RA synovial fluid, and retained their suppressive capacity in this environment. These data show the potential to reset the pathogenic profile of human memory Th cells into non-pathogenic cells with regulatory capacity.

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Section: Discussionmentioning

confidence: 73%

Human Memory Th17 Cell Populations Change Into Anti-inflammatory Cells With Regulatory Capacity Upon Exposure to Active Vitamin D

et al. 2019

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“…Two weeks following infliximab monocyte chemokine CCL2 (MCP-1), but not CCL5 (RANTES), CCL3 (MIP1α) or CCL4 (MIP1β) was reduced when examined by immunohistochemistry (8). Serum CCL2 correlated with the swollen joint count in RA (39), and reduction of serum CCL2 was observed following treatment with infliximab or etanercept (8, 40). However, employing technetium-99m labeled autologous monocytes, no reduction of monocyte influx into the inflamed RA joints was observed 14 days after treatment with adalimumab, even though clinical benefit was observed at this time point (7).…”

Section: Discussionmentioning

confidence: 99%

The Role of Macrophages in the Response to TNF Inhibition in Experimental Arthritis

Huang

Birkett

Doyle

et al. 2018

The Journal of Immunology

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The reduction of synovial tissue macrophages is a reliable biomarker for clinical improvement in patients with rheumatoid arthritis (RA), and macrophages are reduced in synovial tissue shortly after initiation of TNF inhibitors. The mechanism for this initial response is unclear. These studies were performed to identify the mechanisms responsible for the initial reduction of macrophages following TNF inhibition, positing that efflux to draining lymph nodes was involved. RA synovial tissue and synovial fluid macrophages expressed CCR7, which was increased in control macrophages following incubation with TNF-α. Human TNF transgenic (hTNF-Tg) mice were treated with infliximab after development of arthritis. Ankles were harvested and examined by histology, immunohistochemistry, quantitative RT-PCR, ELISA, and flow cytometry. hTNF-Tg mice treated with infliximab demonstrated significant clinical and histologic improvement 3 d after the initiation of therapy, at which time Ly6C macrophages were significantly reduced in the ankles. However, no evidence was identified to support a role of macrophage efflux to draining lymph nodes following treatment with infliximab. In contrast, apoptosis of Ly6C macrophages in the ankles and popliteal lymph nodes, decreased migration of monocytes into the ankles, and a reduction of CCL2 were identified following the initiation of infliximab. These observations demonstrate that Ly6C macrophage apoptosis and decreased ingress of circulating monocytes into the joint are responsible for the initial reduction of macrophages following infliximab treatment in hTNF-Tg mice.

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“…Instead, CCR2 blockage appears to augment the suppression of IFN-γ-induced M1 marker expression. CCL2, a ligand for CCR2, is an inflammatory chemokine that is highly present in the serum of patients with RA relative to the serum of those with osteoarthritis [ 31 ], and a positive correlation has been reported between serum CCR2 concentration and RA disease activity [ 32 ]. Thus, inhibition of the CCR2/CCL2 pathway may more effectively suppress M1 macrophage activity and disease activity in CIA.…”

Section: Discussionmentioning

confidence: 99%

Soluble Siglec-9 suppresses arthritis in a collagen-induced arthritis mouse model and inhibits M1 activation of RAW264.7 macrophages

et al. 2016

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BackgroundThe aim of this study was to assess the effects of soluble sialic acid-binding immunoglobulin-type lectin (sSiglec)-9 on joint inflammation and destruction in a murine collagen-induced arthritis (CIA) model and in monolayer cultures of murine macrophages (RAW264.7 cells and peritoneal macrophages) and fibroblast-like synoviocytes (FLS) derived from patients with rheumatoid arthritis.MethodsDBA/1J mice were immunized with type II collagen. Effects of sSiglec-9 were evaluated using a physiologic arthritis score, histological analysis, serum tumor necrosis factor (TNF)-α concentration, and the proportion of forkhead box P3 (Foxp3)-positive regulatory T (Treg) cells. In vivo biofluorescence imaging was used to assess the distribution of sSiglec-9. Levels of M1 (TNF-α, interleukin [IL]-6, and inducible nitric oxide synthase) and M2 (CD206, Arginase-1, and IL-10) macrophage markers and phosphorylation of intracellular signaling molecules were examined in macrophages, and levels of matrix metalloproteinase (MMP)-1, MMP-3, and MMP-13 were examined in FLS.ResultssSiglec-9 significantly suppressed the clinical and histological incidence and severity of arthritis. The proportion of Foxp3-positive Treg cells significantly improved and serum TNF-α concentration decreased in vivo. Although sSiglec-9 reduced the expression of M1 markers in macrophages, it did not affect the expression of M2 markers and MMPs in FLS. Nuclear factor (NF)-kB p65 phosphorylation was attenuated by sSiglec-9, and chemical blockade of the NF-kB pathway reduced M1 marker expression in RAW264.7 cells.ConclusionsIn this study, we have demonstrated the therapeutic effects of sSiglec-9 in a murine CIA model. The mechanism underlying these effects involves the suppression of M1 proinflammatory macrophages by inhibiting the NF-kB pathway. sSiglec-9 may provide a novel therapeutic option for patients with rheumatoid arthritis refractory to currently available drugs.

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Etanercept reduces the serum levels of macrophage chemotactic protein-1 in patients with rheumatoid arthritis

Cited by 12 publications

References 43 publications

Human Memory Th17 Cell Populations Change Into Anti-inflammatory Cells With Regulatory Capacity Upon Exposure to Active Vitamin D

Human Memory Th17 Cell Populations Change Into Anti-inflammatory Cells With Regulatory Capacity Upon Exposure to Active Vitamin D

The Role of Macrophages in the Response to TNF Inhibition in Experimental Arthritis

Soluble Siglec-9 suppresses arthritis in a collagen-induced arthritis mouse model and inhibits M1 activation of RAW264.7 macrophages

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