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1.
Sci Rep ; 10(1): 780, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964950

RESUMO

Synovial fibroblasts (SF) were reported to produce B cell activating factor (BAFF) in response to stimulation with interferon-γ (IFN-γ) or tumor necrosis factor (TNF). However, the influence of these pro-inflammatory cytokines on other receptors/ligands of the TNF superfamily or associated cytokine receptors in SF has not been investigated yet. Here we show the differential regulation of BAFF (CD257), Fn14 (CD266), TACI (CD267), BAFF-R (CD268), BCMA (CD269), CD40 ligand (CD40L, CD154), IFN-γR (CD119), Leptin receptor (ObR, CD295), VCAM-1 (CD106) and membrane TGF-ß in isolated SF and the impact of IFN-γ/TNF co-incubation on proliferation, IL-6 and IL-8 production. In addition, the impact of differentially stimulated SF on B cell survival in co-cultures was assessed. Surface cytokines and cytokine receptors were detected by flow cytometry. Soluble cytokine receptors and cytokines were quantified by ELISA. Proliferation was assessed by cell titer blue. Murine B cell survival in fibroblast/ B cell co-cultures was determined by annexin V/propidium iodide staining and flow cytometry. IFN-γ together with TNF synergistically and significantly increased the cell surface levels of BAFF, Fn14, TACI, BAFF-R, BCMA, CD40L, ObR and IFN-γR in rheumatoid arthritis SF after 72 h incubation. Soluble BAFF was only induced by IFN-γ and inhibited by TNF. Addition of TWEAK had no influence on proliferation or IL-8 production but decreased TNF-induced IL-6 production, whereas APRIL, BAFF and leptin did not modulate TNF or TNF/IFN-γ-induced proliferation or cytokine production. Proliferation was increased by TNF and further enhanced by the addition of IFN-γ. In co-culture experiments, SF stimulated with TNF/IFN but not TNF or IFN-γ alone increased shedding of VCAM-1 and expression of membrane TGFß, which was associated with reduced survival of murine B cells. IFN-γ and TNF regulate the expression of TNF family member cytokines and associated receptors. Ligation of IFN-γR and Fn14 under pro-inflammatory conditions modulated IL-6/IL-8 production and proliferation. In B cell/SF co-cultures, the combination of TNF/IFN reduced B cell survival possibly via enhanced VCAM-1 shedding and/or increased TGF-ß production. IFN-γ is necessary for the observed effects on B cell survival and SF cytokine production and emphasizes its anti-inflammatory role in rheumatoid arthritis.


Assuntos
Artrite Reumatoide/imunologia , Fator Ativador de Células B/metabolismo , Linfócitos B/citologia , Interferon gama/farmacologia , Membrana Sinovial/citologia , Fator de Necrose Tumoral alfa/farmacologia , Idoso , Animais , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular , Células Cultivadas , Técnicas de Cocultura , Feminino , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Receptores de Citocinas/efeitos dos fármacos , Receptores de Citocinas/metabolismo , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismo
4.
Hamostaseologie ; 38(4): 236-239, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30267387

RESUMO

Thrombi are composed of activated platelets and fibrin, the latter being the final product of the blood coagulation system. Therefore, antithrombotic therapies may either interfere with adhesion, aggregation, secretion or signalling of platelets or with fibrin formation. Established drugs potently inhibit clot formation, but also increase the risk of bleeding. In this review article, we discuss novel strategies for the inhibition of pathological thrombosis while enabling normal haemostasis, thus minimizing the risk of bleeding.


Assuntos
Fibrinolíticos/uso terapêutico , Hemostasia/efeitos dos fármacos , Inibidores da Agregação Plaquetária/uso terapêutico , Trombose/tratamento farmacológico , Animais , Coagulação Sanguínea/efeitos dos fármacos , Fibrinolíticos/efeitos adversos , Hemorragia/induzido quimicamente , Humanos , Terapia de Alvo Molecular , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/efeitos adversos , Trombose/sangue
5.
Nat Commun ; 9(1): 525, 2018 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-29410422

RESUMO

Integrin-based therapeutics have garnered considerable interest in the medical treatment of inflammation. Integrins mediate the fast recruitment of monocytes and neutrophils to the site of inflammation, but are also required for host defense, limiting their therapeutic use. Here, we report a novel monoclonal antibody, anti-M7, that specifically blocks the interaction of the integrin Mac-1 with its pro-inflammatory ligand CD40L, while not interfering with alternative ligands. Anti-M7 selectively reduces leukocyte recruitment in vitro and in vivo. In contrast, conventional anti-Mac-1 therapy is not specific and blocks a broad repertoire of integrin functionality, inhibits phagocytosis, promotes apoptosis, and fuels a cytokine storm in vivo. Whereas conventional anti-integrin therapy potentiates bacterial sepsis, bacteremia, and mortality, a ligand-specific intervention with anti-M7 is protective. These findings deepen our understanding of ligand-specific integrin functions and open a path for a new field of ligand-targeted anti-integrin therapy to prevent inflammatory conditions.


Assuntos
Anticorpos Monoclonais/farmacologia , Inflamação/tratamento farmacológico , Antígeno de Macrófago 1/metabolismo , Terapia de Alvo Molecular/métodos , Animais , Sítios de Ligação , Ligante de CD40/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Inflamação/patologia , Leucócitos/efeitos dos fármacos , Leucócitos/patologia , Masculino , Camundongos Endogâmicos C57BL , Neutrófilos/efeitos dos fármacos , Sepse/tratamento farmacológico
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