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1.
J Transl Med ; 19(1): 190, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-33941197

RESUMO

BACKGROUND: Endogenous Peptide Inhibitor of CXCR4 (EPI-X4) is a natural antagonist of the CXC chemokine receptor 4 (CXCR4). EPI-X4 is a 16-mer peptide that is released from human serum albumin (HSA) by acidic aspartic proteases such as Cathepsin D and E. Since human serum albumin (HSA) is an important medicinal substance we asked whether different pharmaceutical HSA products contain EPI-X4 which could have been generated during manufacturing and whether HSA can serve as a substrate for cathepsins despite of the presence of stabilizers like caprylate. METHODS: Eight pharmaceutical HSA preparations representing all currently used fractionation technologies were analyzed. The previously described specific EPI-X4 ELISA was used for quantification; in vitro EPI-X4 generation by acidification in the presence or absence of cathepsins was followed by quantification with ELISA. RESULTS: None of the pharmaceutical HSA preparations tested contained EPI-X4. Acidification of HSA did not generate EPI-X4. Addition of cathepsins D and E to acidified HSA yielded high concentrations of EPI-X4 in all HSA preparations, indistinguishable between individual products. CONCLUSION: Medicinal HSA preparations per se do not contain EPI-X4, but will replenish its precursor which can be cleaved to EPI-X4 in vivo, environmental conditions permitting.


Assuntos
Preparações Farmacêuticas , Receptores CXCR4 , Humanos , Peptídeos , Albumina Sérica Humana , Transdução de Sinais
2.
Curr Protein Pept Sci ; 16(1): 77-86, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25692849

RESUMO

A key event in inflammatory disease is the transendothelial recruitment of leukocytes from the circulation to the site of inflammation. Intense research in the past decades indicates that the polyanionic carbohydrate heparan sulphate (HS) modulates multiple steps in the leukocyte recruitment cascade. Leukocyte recruitment is initiated by endothelial cell activation and presentation of chemokines to rolling leukocytes, which, via integrin activation, results in adhesion and diapedesis through the vessel wall. Heparan sulfate proteoglycans (HSPGs) immobilize the chemokines on the luminal endothelial cells, rendering them more robust against mechanical or hydrodynamic perturbations. During inflammation, endothelial HSPGs serve as ligands to L-selectin on leukocytes, transport chemokines in a basolateral to apical direction across the endothelium, and present chemokines at the luminal surface of the endothelium to circulating cells. HSPGs also promote chemokine oligomerization, which influences chemokine receptor signaling. Furthermore, proteoglycans of the syndecan family are involved in modulating integrin-mediated tight adhesion of leukocytes to the endothelium. Creation of a chemokine gradient by a localized chemokine release influences the speed of leukocyte recruitment from the blood to the tissue by attracting crawling neutrophils to optimal sites for transmigration. The directionality of intraluminal crawling is thought to be influenced by both mechanotactic and haptotactic signals, which are modulated by HS-dependent signaling processes. Finally, diapedesis is influenced by HS regarding transendothelial chemokine gradient formation and integrin- CAM interactions, and further enhanced by heparanase-mediated degradation of the endothelial basement membrane. Overall, the multifunctional role of HS in inflammation marks it as a potential target of glycan-centered therapeutic approaches.


Assuntos
Quimiotaxia de Leucócito/imunologia , Heparitina Sulfato/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Leucócitos/imunologia , Leucócitos/metabolismo , Animais , Adesão Celular/imunologia , Humanos , Migração e Rolagem de Leucócitos/imunologia , Migração Transendotelial e Transepitelial/imunologia
3.
J Biol Chem ; 288(18): 12699-711, 2013 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-23460644

RESUMO

The proteoglycan decorin modulates leukocyte recruitment during delayed-type hypersensitivity responses. Decorin-deficient (Dcn(-/-)) mice show reduced edema formation during the first 24 h with a concurrent attenuated recruitment of CD8(+) leukocytes in the inflamed Dcn(-/-) ears. The aim of this study was to elucidate the molecular pathways affected by the loss of decorin. In vivo, reduced numbers of CD8(+) cells in Dcn(-/-) ears correlated with a reduced interferon-γ (Ifn-γ) and CXCL-10 expression. In vitro, Dcn(-/-) lymphocytes displayed an increased adhesion to brain microvascular (bEnd.3) endothelial cells. Decorin treatment of bEnd.3 increased Icam1 and down-regulated Vcam1 expression after TNF-α stimulation. However, Dcn(-/-) and wild-type lymphocytes produced IFN-γ after activation with CD3ε. Upon incubation with decorin, endothelial cells and fibroblasts responded differently to IFN-γ and TNF-α; CCL2 in bEnd.3 cells was more prominently up-regulated by TNF-α compared with IFN-γ. Notably, both factors were more potent in the presence of decorin. Compared with TNF-α, IFN-γ treatment induced significantly more CXCL-10, and both factors increased synthesis of CXCL-10 in the presence of decorin. The response to IFN-γ was similar in Dcn(-/-) and wild-type fibroblasts, an additional source of CXCL-10. However, addition of decorin yielded significantly more CXCL-10. Notably, decorin increased the stability of IFN-γ in vitro and potentiated IFN-γ-induced activation of STAT-1. Furthermore, only dermatan sulfate influenced IFN-γ signaling by significantly increasing CXCL-10 expression in contrast to decorin protein core alone. Our data demonstrate that decorin modulates delayed-type hypersensitivity responses by augmenting the induction of downstream effector cytokines of IFN-γ and TNF-α, thereby influencing the recruitment of CD8(+) lymphocytes into the inflamed tissue.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Decorina/imunologia , Hipersensibilidade Tardia/imunologia , Interferon gama/imunologia , Animais , Complexo CD3/genética , Complexo CD3/imunologia , Complexo CD3/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/patologia , Quimiocina CCL2/biossíntese , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Quimiocina CXCL10/biossíntese , Quimiocina CXCL10/genética , Quimiocina CXCL10/imunologia , Decorina/genética , Decorina/metabolismo , Modelos Animais de Doenças , Fibroblastos/imunologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Humanos , Hipersensibilidade Tardia/genética , Hipersensibilidade Tardia/metabolismo , Hipersensibilidade Tardia/patologia , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Interferon gama/biossíntese , Interferon gama/genética , Camundongos , Camundongos Knockout , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
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