scholarly journals ADAM17 deficiency by mature neutrophils has differential effects on L-selectin shedding

Blood ◽  
2006 ◽  
Vol 108 (7) ◽  
pp. 2275-2279 ◽  
Author(s):  
Ying Li ◽  
Jennifer Brazzell ◽  
Amy Herrera ◽  
Bruce Walcheck
Keyword(s):  
Fetal Liver ◽  
Surface Expression ◽  
Ectodomain Shedding ◽  
Blood Leukocytes ◽  
Fetal Liver Cells ◽  
Metalloprotease Inhibitor ◽  
Factor Α ◽  
And Control ◽  
Necrosis Factor

Abstract L-selectin directs neutrophils to sites of inflammation, and upon their activation, surface expression of the receptor is rapidly down-regulated by ectodomain shedding. Tumor necrosis factor–α–converting enzyme (TACE, or ADAM17) is a sheddase of L-selectin; however, Adam17 gene targeting (ADAM17ΔZn/ΔZn) in mice is perinatal lethal and its role in L-selectin shedding by mature neutrophils has not been determined. This was addressed here by using radiation-chimeric mice reconstituted with ADAM17ΔZn/ΔZn fetal liver cells. ADAM17-deficient neutrophils, monocytes, and lymphocytes failed to shed L-selectin in response to PMA, as did neutrophils infiltrating the inflamed peritoneum. In addition, the absence of functional ADAM17 resulted in significantly increased levels of L-selectin surface expression by peripheral-blood leukocytes, indicating the sheddase also plays a role in the constitutive cleavage of L-selectin. Interestingly, not all manners of L-selectin turnover required ADAM17. Plasma L-selectin levels were similar between ADAM17ΔZn/ΔZn-chimeric and control mice, as was the shedding of L-selectin by neutrophils undergoing spontaneous apoptosis. The latter process, however, was diminished by a metalloprotease inhibitor, indicating the role of a sheddase other than ADAM17. Together, our data reveal that L-selectin's surface density on neutrophils is regulated by ADAM17, but homeostatic L-selectin cleavage is not.

Metalloprotease-disintegrins: modular proteins capable of promoting cell-cell interactions and triggering signals by protein-ectodomain shedding

1999 ◽  
Vol 112 (21) ◽  
pp. 3603-3617 ◽  
Author(s):  
J. Schlondorff ◽  
C.P. Blobel
Keyword(s):  
Tumor Necrosis ◽  
Ectodomain Shedding ◽  
Membrane Glycoproteins ◽  
Tnf Α ◽  
Disintegrin Domain ◽  
Protein Ectodomain Shedding ◽  
Integrin Ligands ◽  
Factor Α ◽  
Necrosis Factor

Metalloprotease-disintegrins (ADAMs) have captured our attention as key players in fertilization and in the processing of the ectodomains of proteins such as tumor necrosis factor (α) (TNF(α)), and because of their roles in Notch-mediated signaling, neurogenesis and muscle fusion. ADAMs are integral membrane glycoproteins that contain a disintegrin domain, which is related to snake-venom integrin ligands, and a metalloprotease domain (which can contain or lack a catalytic site). Here, we review and critically discuss current topics in the ADAMs field, including the central role of fertilin in fertilization, the role of the TNF(α) convertase in protein ectodomain processing, the role of Kuzbanian in Notch signaling, and links between ADAMs and processing of the amyloid-precursor protein.

Monocytes recruited into the alveolar air space of mice show a monocytic phenotype but upregulate CD14

2001 ◽  
Vol 280 (1) ◽  
pp. L58-L68 ◽  
Author(s):  
Ulrich Maus ◽  
Susanne Herold ◽  
Heidrun Muth ◽  
Regina Maus ◽  
Leander Ermert ◽  
...  
Keyword(s):  
Human Monocyte ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Blood Monocytes ◽  
Blood Leukocytes ◽  
Alveolar Air ◽  
Inflammatory Conditions ◽  
Air Space ◽  
Factor Α ◽  
Necrosis Factor

The evaluation of monocytes recruited into the alveolar space under both physiological and inflammatory conditions is hampered by difficulties in discriminating these cells from resident alveolar macrophages (rAMs). Using the intravenous injected fluorescent dye PKH26, which accumulated in rAMs without labeling blood leukocytes, we developed a technique that permits the identification, isolation, and functional analysis of monocytes recruited into lung alveoli of mice. Alveolar deposition of murine JE, the homologue of human monocyte chemoattractant protein (MCP)-1 (JE/MCP-1), in mice provoked an alveolar influx of monocytes that were recovered by bronchoalveolar lavage and separated from PKH26-stained rAMs by flow cytometry. Alveolar recruited monocytes showed a blood monocytic phenotype as assessed by cell surface expression of F4/80, CD11a, CD11b, CD18, CD49d, and CD62L. In contrast, CD14 was markedly upregulated on alveolar recruited monocytes together with increased tumor necrosis factor-α message, discriminating this monocyte population from peripheral blood monocytes and rAMs. Thus monocytes recruited into the alveolar air space of mice in response to JE/MCP-1 keep phenotypic features of blood monocytes but upregulate CD14 and are “primed” for enhanced responsiveness to endotoxin with increased cytokine expression.

scholarly journals Fetal hemopoiesis in diffusion chamber cultures. III. The effect of neutropenia

Blood ◽  
1976 ◽  
Vol 48 (2) ◽  
pp. 283-291 ◽  
Author(s):  
M Symann ◽  
P Quesenberry ◽  
A Fontebuoni ◽  
D Howard ◽  
M Ryan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Fetal Liver ◽  
Diffusion Chamber ◽  
Colony Growth ◽  
Humoral Factors ◽  
Marked Variability ◽  
Proliferation And Differentiation ◽  
Fetal Liver Cells ◽  
And Control

Abstract Proliferation and differentiation of granulocytes, macrophages, and both myeloid committed (CFC) and pluripotent (CFU) stem cells in diffusion chamber (DC) cultures of fetal liver were studied in order to evaluate the role of circulating humoral factors in the control of fetal myelopoiesis. When DC with fetal liver cells were implanted into mice rendered neutropenic by pretreatment with cyclophosphamide, more granulocytes and CFC were produced through day 10 as compared to DC implanted into saline pretreated control hosts. A difference in CFU recovery from fetal liver suspensions grown in DC implanted into neutropenic and control hosts was not seen until day 10. Serum CSF concentrations were increased in neutropenic as compared to control host mice 2 and 3 days after implantation of DC. Levels of serum inhibitors of colony growth showed marked variability but, in general, were similar in both groups. These data provide evidence that fetal CFC and fetal myelopoiesis are influenced by a circulating humoral factor present in neutropenic serum. CSF may be the factor, although the data presented in this paper do not establish this with any certainty.

scholarly journals Fetal hemopoiesis in diffusion chamber cultures. III. The effect of neutropenia

Blood ◽  
1976 ◽  
Vol 48 (2) ◽  
pp. 283-291
Author(s):  
M Symann ◽  
P Quesenberry ◽  
A Fontebuoni ◽  
D Howard ◽  
M Ryan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Fetal Liver ◽  
Diffusion Chamber ◽  
Colony Growth ◽  
Humoral Factors ◽  
Marked Variability ◽  
Proliferation And Differentiation ◽  
Fetal Liver Cells ◽  
And Control

Proliferation and differentiation of granulocytes, macrophages, and both myeloid committed (CFC) and pluripotent (CFU) stem cells in diffusion chamber (DC) cultures of fetal liver were studied in order to evaluate the role of circulating humoral factors in the control of fetal myelopoiesis. When DC with fetal liver cells were implanted into mice rendered neutropenic by pretreatment with cyclophosphamide, more granulocytes and CFC were produced through day 10 as compared to DC implanted into saline pretreated control hosts. A difference in CFU recovery from fetal liver suspensions grown in DC implanted into neutropenic and control hosts was not seen until day 10. Serum CSF concentrations were increased in neutropenic as compared to control host mice 2 and 3 days after implantation of DC. Levels of serum inhibitors of colony growth showed marked variability but, in general, were similar in both groups. These data provide evidence that fetal CFC and fetal myelopoiesis are influenced by a circulating humoral factor present in neutropenic serum. CSF may be the factor, although the data presented in this paper do not establish this with any certainty.

Combination of IL-17 and TNFα induces a pro-inflammatory, pro-coagulant and pro-thrombotic phenotype in human endothelial cells

2012 ◽  
Vol 71 (5) ◽  
pp. 768-776 ◽  
Author(s):  
Arnaud Hot ◽  
Vanina Lenief ◽  
Pierre Miossec
Keyword(s):  
Platelet Aggregation ◽  
Migration And Invasion ◽  
Human Endothelial Cells ◽  
Qrt Pcr ◽  
Functional Assays ◽  
Affymetrix Microarrays ◽  
Stromal Cell Derived Factor ◽  
Factor Α ◽  
Necrosis Factor

ObjectiveCardiovascular events remain the leading cause of death in rheumatoid arthritis (RA). To study the role of cytokines in these observations, the effects of tumour necrosis factor α (TNFα) and interleukin (IL)-17, a classical and a new key player in RA, were assessed in endothelial cell (EC) dysfunction.MethodsPrimary human EC were treated with IL-17 alone or combined with TNFα. mRNA expression was quantified by qRT PCR and Affymetrix microarrays. The role of IL-17 was studied using functional assays of platelet aggregation, EC migration and invasion.ResultsIL-17 alone induced 248 pro-inflammatory genes and 9803, when combined with TNFα. IL-17 plus TNFα induced synergistically chemokine genes such as CCL5, IL-8 and cytokine genes such as IL-6. In contrast, IL-17 decreased genes involved in the regulation of inflammation such as IL-33. IL-17 induced EC migration and invasion in synergy with TNFα. Such invasion was inhibited with an antiCXCR4 antibody, indicating the contribution of the stromal cell-derived factor-1/C-X-C chemokine receptor type 4 axis. Supernatants of IL-17-treated EC induced strong platelet aggregation. IL-17 inhibited endothelial CD39/ATPDase expression, an inhibitor of platelet activation. Finally, IL-17 enhanced genes critical for coagulation such as tissue factor and decreased thrombomodulin, leading to a pro-thrombotic state.ConclusionThese results indicate that IL-17 specifically when combined with TNFα has major pro-coagulant and pro-thrombotic effects on vessels.

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