Regulation of cytokine expression and leukotriene formation in human basophils by growth factors, chemokines and chemotactic agonists

Ochensberger, Brigitte; Tassera, Lorenz; Bifrare, Delphine; Rihs, Silvia; Dahinden, Clemens A.

doi:10.1002/(sici)1521-4141(199901)29:01<11::aid-immu11>3.0.co;2-b

Cited by 92 publications

(74 citation statements)

References 41 publications

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“…The results of our and other laboratories have demonstrated the expression of multiple chemokine receptors in basophils (13,16,20), and our previous functional survey demonstrated that CCR3 ligands are mainly responsible for the migratory responses of resting basophils (13). Fig.…”

Section: Basophil Tem By Chemokinesmentioning

confidence: 62%

Transendothelial Migration of Human Basophils

Iikura

Ebisawa

Yamaguchi

et al. 2004

The Journal of Immunology

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During allergic reactions, basophils migrate from the blood compartment to inflammatory sites, where they act as effector cells in concert with eosinophils. Because transendothelial migration (TEM) represents an essential step for extravasation of cells, for the first time we have studied basophil TEM using HUVEC. Treatment of HUVEC with IL-1β significantly enhanced basophil TEM, which was further potentiated by the presence of a CCR3-specific ligand, eotaxin/CCL11. In addition to CCR3 ligands, MCP-1/CCL2 was also active on basophil TEM. Although stromal cell-derived factor-1/CXCL12, a CXCR4 ligand, failed to induce TEM in freshly isolated basophils, it caused strong TEM in 24-h cultured cells. IL-3 enhanced basophil TEM by increasing the chemokinetic response. Spontaneous TEM across activated HUVEC was inhibited by treatment of cells with anti-CD18 mAb, but not with anti-CD29 mAb, and also by treatment of HUVEC with anti-ICAM-1 mAb. Anti-VCAM-1 mAb alone failed to inhibit TEM, but showed an additive inhibitory effect in combination with anti-ICAM-1 mAb. In contrast, eotaxin- and IL-3-mediated TEM was significantly inhibited by anti-CD29 mAb as well as anti-CD18 mAb. These results indicate that β2 integrins play the primary role in basophil TEM, but β1 integrins are also involved, especially in TEM of cytokine/chemokine-stimulated basophils. In conclusion, the regulatory profile of basophil TEM is very similar to that reported for eosinophils. Our results thus support the previous argument for a close relationship between basophils and eosinophils and suggest that the in vivo kinetics of these two cell types are similar.

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Section: Basophil Tem By Chemokinesmentioning

confidence: 62%

Transendothelial Migration of Human Basophils

Iikura

Ebisawa

Yamaguchi

et al. 2004

The Journal of Immunology

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“…Eotaxin/CCL11, a natural antagonist of CCR2, was recently shown to induce signal transduction via the ERK-1/2 pathway (30). Human basophils also express CCR2 (31) and can be activated via CCR2, resulting in shape changes (31) and the release of cytokines and leukotriene C 4 (32).…”

Section: Discussionmentioning

confidence: 99%

Targeting of Gr‐1+,CCR2+ monocytes in collagen‐induced arthritis

Brühl¹,

Cihak²,

Plachý

et al. 2007

Arthritis & Rheumatism

108

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Objective. The chemokine receptor CCR2 is highly expressed on monocytes and considered a promising target for treatment of rheumatoid arthritis. However, blockade of CCR2 with a monoclonal antibody (mAb) during progression of collagen-induced arthritis results in a massive aggravation of the disease. In this study we investigated why CCR2 antibodies have proinflammatory effects, how these effects can be avoided, and whether CCR2؉ monocytes are useful targets in the treatment of arthritis.Methods. Arthritis was induced in DBA/1 mice by immunization with type II collagen. Mice were treated with mAb against CCR2 (MC-21), IgE, or isotype control antibodies at various time points. Activation of basophils and depletion of monocyte subsets were determined by fluorescence-activated cell sorter analysis and enzyme-linked immunosorbent assay.Results. Crosslinkage of CCR2 activated basophils to release interleukin-6 (IL-6) and IL-4. In vivo, IL-6 release occurred only after exposure to high doses of MC-21, whereas application of low doses of the mAb circumvented the release of IL-6. Regardless of the dose level used, the antibody MC-21 efficiently depleted Gr-1؉,CCR2؉ monocytes from the synovial tissue, peripheral blood, and spleen of DBA/1 mice. Activation of basophils with high doses of MC-21 or with antibodies against IgE resulted in a marked aggravation of collagen-induced arthritis and an increased release of IL-6. In contrast, low-dose treatment with MC-21 in this therapeutic setting had no effect on IL-6 and led to marked improvement of arthritis.Conclusion. These results show that depletion of CCR2؉ monocytes may prove to be a therapeutic option in inflammatory arthritis, as long as the dosedependent proinflammatory effects of CCR2 mAb are taken into account.CCR2, a chemokine (CC motif) receptor, is considered a promising target for disorders such as multiple sclerosis, type II diabetes, and rheumatoid arthritis, and Phase I and II clinical trials are currently in progress (1). Data on CCR2 expression in humans and results from studies of CCR2-deficient mice (2-4) support the blockade of CCR2 as an effective strategy in the treatment of multiple sclerosis and diabetes. In patients with rheumatoid arthritis, we and other investigators have found an increased frequency of CCR2ϩ cells in the synovial fluid and synovial tissue (5-7). In addition, increased levels of the CCR2 ligand monocyte chemoattractant protein 1 (MCP-1; CCL2) were found in patients with rheumatoid arthritis (8). Monocytes are thought to play a major role in joint destruction, and their recruitment to sites of inflammation is crucially dependent on CCR2, as shown in several murine disease models (9-12).However, thus far, data from murine models of collagen-induced arthritis do not support CCR2 as a target for treatment of rheumatoid arthritis. We have previously shown that treatment with a blocking monoDrs. Brühl, Luckow,

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“…Besides CCR3, which is believed to mediate principally cell recruitment and chemotaxis (as opposed to degranulation) (16,17,27), basophils also express other CCRs, including CCR1 and CCR2. Although the role of CCR1 is still unclear, CCR2 is strongly linked to histamine release and leukotriene secretion (16,22).…”

Section: Basophil Responses To Chemokinesmentioning

confidence: 99%

Basophil Responses to Chemokines Are Regulated by Both Sequential and Cooperative Receptor Signaling

Heinemann

Hartnell

Stubbs

et al. 2000

The Journal of Immunology

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To investigate human basophil responses to chemokines, we have developed a sensitive assay that uses flow cytometry to measure leukocyte shape change as a marker of cell responsiveness. PBMC were isolated from the blood of volunteers. Basophils were identified as a single population of cells that stained positive for IL-3Rα (CDw123) and negative for HLA-DR, and their increase in forward scatter (as a result of cell shape change) in response to chemokines was measured. Shape change responses of basophils to chemokines were highly reproducible, with a rank order of potency: monocyte chemoattractant protein (MCP) 4 (peak at <1 nM) ≥ eotaxin-2 = eotaxin-3 ≥ eotaxin > MCP-1 = MCP-3 > macrophage-inflammatory protein-1α > RANTES = MCP-2 = IL-8. The CCR4-selective ligand macrophage-derived chemokine did not elicit a response at concentrations up to 10 nM. Blocking mAbs to CCR2 and CCR3 demonstrated that responses to higher concentrations (>10 nM) of MCP-1 were mediated by CCR3 rather than CCR2, whereas MCP-4 exhibited a biphasic response consistent with sequential activation of CCR3 at lower concentrations and CCR2 at 10 nM MCP-4 and above. In contrast, responses to MCP-3 were blocked only in the presence of both mAbs, but not after pretreatment with either anti-CCR2 or anti-CCR3 mAb alone. These patterns of receptor usage were different from those seen for eosinophils and monocytes. We suggest that cooperation between CCRs might be a mechanism for preferential recruitment of basophils, as occurs in tissue hypersensitivity responses in vivo.

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Regulation of cytokine expression and leukotriene formation in human basophils by growth factors, chemokines and chemotactic agonists

Cited by 92 publications

References 41 publications

Transendothelial Migration of Human Basophils

Transendothelial Migration of Human Basophils

Targeting of Gr‐1+,CCR2+ monocytes in collagen‐induced arthritis

Basophil Responses to Chemokines Are Regulated by Both Sequential and Cooperative Receptor Signaling

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