scholarly journals TSG-6 in extracellular vesicles from canine mesenchymal stem/stromal is a major factor in relieving DSS-induced colitis

2019 ◽  
Author(s):  
Ju-Hyun An ◽  
Woo-Jin Song ◽  
Qiang Li ◽  
Min-Ok Ryu ◽  
A-Ryung Nam ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Qrt Pcr ◽  
Tnf Α ◽  
Key Factor ◽  
Ifn Γ ◽  
Underlying Mechanisms ◽  
Factor Α ◽  
Necrosis Factor

AbstractMesenchymal stem/stromal cell (MSC)-derived extracellular vesicles (EV) have been reported to be beneficial against dextran sulfate sodium (DSS)-induced colitis in mice. However, the underlying mechanisms have not been fully elucidated. We hypothesize that the tumor necrosis factor-α-stimulated gene/protein 6 (TSG-6) in EVs is a key factor influencing the alleviation of colitis symptoms. DSS-induced colitis mice (C57BL/6, male, n = 6-8/group) were intraperitoneally administered EVs (100 ug/mice) on day 1, 3, and 5; colon tissues were collected on day 10 for histopathological, qRT-PCR, western blot, and immunofluorescence analyses. In mice injected with EV, inflammation was alleviated. Indeed, EVs regulated the levels of pro- and anti-inflammatory cytokines, such as TNF-α, IL-1β, IFN-γ, IL-6, and IL-10 in inflamed colons. However, when injected with TSG-6 depleted EV, the degree of inflammatory relief was reduced. Furthermore, TSG-6 in EVs plays a key role in increasing regulatory T cells (Tregs) in the colon. In conclusion, this study shows that TSG-6 in EVs is a major factor in the relief of DSS-induced colitis, by increasing the number of Tregs in the colon.

scholarly journals Differential Deactivation of Human Dendritic Cells by Endotoxin Desensitization: Role of Tumor Necrosis Factor-α and Prostaglandin E2

Blood ◽  
1998 ◽  
Vol 91 (9) ◽  
pp. 3112-3117 ◽  
Author(s):  
Claudia Rieser ◽  
Christine Papesh ◽  
Manfred Herold ◽  
Günther Böck ◽  
Reinhold Ramoner ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Prostaglandin E2 ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Mixed Leukocyte Reaction ◽  
Tnf Α ◽  
Ifn Γ ◽  
Factor Α ◽  
Antigen Presenting ◽  
Necrosis Factor

The endotoxin (lipopolysaccharide)-induced cytokine response is followed by a state of unresponsiveness to lipopolysaccharide (LPS) referred to as LPS tolerance or endotoxin desensitization. LPS tolerance, which can be experimentally induced in vitro and in vivo, is also known to occur in septic disease. Here, we evaluated whether dendritic cells (DC), the most potent antigen-presenting cells, are also subject to this phenomenon. Single doses of LPS added at the initiation of DC culture inhibited in a dose-dependent fashion the production of tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), and IL-12, but not the production of IL-8, in response to a second LPS challenge in day-5 DC. In addition, the LPS-induced expression of the CD83 maturation antigen was inhibited in these cells. Moreover, the endocytic activity of DC generated in the presence of LPS was dramatically reduced. DC desensitized with LPS were potent stimulators of T-cell proliferation but poor inducers of interferon-γ (IFN-γ) production in the allogeneic mixed leukocyte reaction. TNF-α and prostaglandin E2, two major products of LPS stimulation, could replace LPS for the induction of tolerance to LPS. Moreover, treatment of desensitized DC with TNF-α plus prostaglandin E2 fully restored CD83 expression and partially restored IL-12 production as well as the IFN-γ–inducing activity of DC in the mixed leukocyte reaction. Our data show that human DC are highly susceptible to the induction of LPS tolerance, which seems to be a state of differential deactivation in which some functions are impaired whereas others are retained. Tolerization at the level of the professional antigen-presenting cell by inflammatory mediators may play an important role in septic disease and in the origin of cancers associated with chronic inflammation.

The Augmented Productions of Neopterin and Cytokines from Macrophages/monocytes in vitro

Pteridines ◽  
1996 ◽  
Vol 7 (3) ◽  
pp. 72-76
Author(s):  
Tadashi Lizuka ◽  
Mitsuyo Sasaki ◽  
Hitomi Kamisako ◽  
Ko Oishi ◽  
Shigeru Uemura ◽  
...  
Keyword(s):  
Kawasaki Disease ◽  
Interleukin 1 ◽  
Poly I:C ◽  
Recombinant Interferon ◽  
Preliminary Examination ◽  
Tnf Α ◽  
Ifn Γ ◽  
Factor Α ◽  
Necrosis Factor

Summary In Kawasaki disease patients, increases in excretion of urinary neopterin coincided with fever and monocytosis in peripheral blood. We examined the products of neopterin, tumor necrosis factor-α (TNFα) and Interleukin-1 β (1L-1β) from healthy adult macrophages/monocytes (Mφ>/M), after stimulation with several activators to obtain some understanding of Kawasaki disease. Upon stimulation with either lipopolysaccharide (LPS) or polyinosinate-polycytidylate (Poly I:C), the Mφ/M released neopterin and pyogenic products (TNF-α or 1L-1β). The release of neopterin was eliminated by the addition of the anti-interferon-y antibody. The production of both TNF-α, 1L-1β and neopterin from Mφ/M upon stimulation of LPS was augmented in a co-culture with low dose recombinant interferon-y (rIFN-γ). Upon stimulation with rIFN-γ alone, however, the Mφ/M released neopterin but not the pyogenic products. A preliminary examination failed to detect. any difference in the response of the Mφ/M in adults annd children after stimulation with LPS. We concluded that some endotoxins could trigger the onset of Kawasaki disease and that endogenous IFN-γ can play an important role in the abnormality of Kawasaki disease patients

Systemic Sclerosis Fibroblasts Show Specific Alterations of Interferon-γ and Tumor Necrosis Factor-α-induced Modulation of Interleukin 6 and Chemokine Ligand 2

2012 ◽  
Vol 39 (5) ◽  
pp. 979-985 ◽  
Author(s):  
ALESSANDRO ANTONELLI ◽  
POUPAK FALLAHI ◽  
SILVIA MARTINA FERRARI ◽  
DILIA GIUGGIOLI ◽  
MICHELE COLACI ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Tumor Necrosis Factor ◽  
Interleukin 6 ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Interferon Γ ◽  
Tnf Α ◽  
Ifn Γ ◽  
Factor Α ◽  
Necrosis Factor

Objective.We evaluated the effect of interferon-γ (IFN-γ) and/or tumor necrosis factor-α (TNF-α) on the secretion of prototype proinflammatory cytokine interleukin 6 (IL-6), compared to T-helper 1 [Th1; chemokine (C-X-C motif) ligand 10 (CXCL10)] or Th2 [chemokine (C-C motif) ligand 2 (CCL2)] chemokines, in primary cultured fibroblasts from patients with systemic sclerosis (SSc) at an early stage of the disease.Methods.Fibroblast cultures from 5 SSc patients (disease duration < 2 yrs) and 5 healthy controls were evaluated for the production of IL-6, CXCL10, and CCL2 at the basal level and after stimulation with IFN-γ and/or TNF-α.Results.SSc fibroblasts basally produced higher levels of IL-6 than controls, while no difference was observed about CCL2 and CXCL10. TNF-α was able to dose-dependently induce IL-6 and CCL2 secretion in SSc, but not in control fibroblasts. By stimulation with increasing doses of IFN-γ, SSc fibroblasts were induced to secrete CCL2 and CXCL10, while no effect was observed on IL-6. The combination of IFN-γ and TNF-α induced a strong secretion of IL-6 and CCL2 in SSc fibroblasts but not in controls. In contrast, the synergistic effect of IFN-γ and TNF-α on CXCL10 secretion was similar in SSc fibroblasts and in controls.Conclusion.SSc fibroblasts participate in the self-perpetuation of inflammation by releasing IL-6, CXCL10, and CCL2 under the influence of IFN-γ and/or TNF-α. SSc fibroblasts are more active than controls in the secretion of IL-6 at baseline, and in the production of IL-6 and CCL2 under the combined IFN-γ/TNF-α stimulation.

scholarly journals Proinflammatory cytokines tumor necrosis factor-α and interferon-γ alter tight junction structure and function in the rat parotid gland Par-C10 cell line

2008 ◽  
Vol 295 (5) ◽  
pp. C1191-C1201 ◽  
Author(s):  
Olga J. Baker ◽  
Jean M. Camden ◽  
Robert S. Redman ◽  
Jonathan E. Jones ◽  
Cheikh I. Seye ◽  
...  
Keyword(s):  
Receptor Agonist ◽  
Interferon Γ ◽  
Anion Secretion ◽  
Cell Monolayers ◽  
Tnf Α ◽  
Rat Parotid Gland ◽  
Ifn Γ ◽  
Rat Parotid ◽  
Factor Α ◽  
Necrosis Factor

Sjögren's syndrome (SS) is an autoimmune disorder characterized by inflammation and dysfunction of salivary glands, resulting in impaired secretory function. The production of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) is elevated in exocrine glands of patients with SS, although little is known about the effects of these cytokines on salivary epithelial cell functions necessary for saliva secretion, including tight junction (TJ) integrity and the establishment of transepithelial ion gradients. The present study demonstrates that chronic exposure of polarized rat parotid gland (Par-C10) epithelial cell monolayers to TNF-α and IFN-γ decreases transepithelial resistance (TER) and anion secretion, as measured by changes in short-circuit current ( Isc) induced by carbachol, a muscarinic cholinergic receptor agonist, or UTP, a P2Y2 nucleotide receptor agonist. In contrast, TNF-α and IFN-γ had no effect on agonist-induced increases in the intracellular calcium concentration [Ca2+]i in Par-C10 cells. Furthermore, treatment of Par-C10 cell monolayers with TNF-α and IFN-γ increased paracellular permeability to normally impermeant proteins, altered cell and TJ morphology, and downregulated the expression of the TJ protein, claudin-1, but not other TJ proteins expressed in Par-C10 cells. The decreases in TER, agonist-induced transepithelial anion secretion, and claudin-1 expression caused by TNF-α, but not IFN-γ, were reversible by incubation of Par-C10 cell monolayers with cytokine-free medium for 24 h, indicating that IFN-γ causes irreversible inhibition of cellular activities associated with fluid secretion in salivary glands. Our results suggest that cytokine production is an important contributor to secretory dysfunction in SS by disrupting TJ integrity of salivary epithelium.

scholarly journals Propofol attenuated the effect of TNF-α on occludin expression by inhibiting HIF-1α/VEGF/VEGFR-2/ERK signaling pathway in hCMEC/D3 cells

2019 ◽  
Author(s):  
Yue Zhang ◽  
Xiaowei Ding ◽  
Changhong Miao ◽  
Jiawei Chen
Keyword(s):  
Signaling Pathway ◽  
Cell Counting ◽  
Erk Signaling ◽  
Microvascular Endothelial Cell ◽  
Tight Junction Proteins ◽  
Tnf Α ◽  
Underlying Mechanisms ◽  
Factor Α ◽  
Necrosis Factor ◽  
Junction Proteins

Abstract Purpose: The levels of tight junction proteins (TJs), especially occludin, correlate with blood-brain barrier (BBB) disruption caused by inflammation in central nervous system (CNS). It has been reported that propofol, the most commonly used anesthetic, could inhibit inflammation response in CNS. In this study, we investigated the effects of tumor necrosis factor-α(TNF-α) and propofol on occludin expression in human cerebral microvascular endothelial cell line, D3 clone (hCMEC/D3 cells), and explored the underlying mechanisms. Methods: The hCMEC/D3 cells were treated with propofol, followed by TNF-α. The expression and phosphorylation of Hif-1α, VEGF, VEGFR-2, ERK, p38MAPK and occludin were measured by Western blot analysis. The cell viability of hCMEC/D3 cells was measured by cell counting kit-8. Results: TNF-α (10 ng/ml, 4 h) significantly decreased the expression of occludin, which was attenuated by propofol (25 μM). TNF-α induced Hif-1α/VEGF/VEGFR-2/ERK signaling pathway, while propofol could inhibit it. TNF-α induced the phosphorylation of p38MAPK, while propofol had no effect on it. In addition, the inhibitors of Hif-1α, VEGF, VEGFR-2, and ERK could reduce the effect of TNF-α on occludin expression. Conclusion: TNF-α could decrease the expression of occludin via activating Hif-1α/VEGF/VEGFR-2/ERK signaling pathway, which was attenuated by propofol.

scholarly journals Propofol attenuated the effect of TNF-α on occludin expression by inhibiting HIF-1α/VEGF/VEGFR-2/ERK signaling pathway in hCMEC/D3 cells

2019 ◽  
Author(s):  
Yue Zhang ◽  
Xiaowei Ding ◽  
Changhong Miao ◽  
Jiawei Chen
Keyword(s):  
Signaling Pathway ◽  
Cell Counting ◽  
Erk Signaling ◽  
Microvascular Endothelial Cell ◽  
Tight Junction Proteins ◽  
Tnf Α ◽  
Underlying Mechanisms ◽  
Factor Α ◽  
Necrosis Factor ◽  
Junction Proteins

Abstract Background: The levels of tight junction proteins (TJs), especially occludin, correlate with blood-brain barrier (BBB) disruption caused by inflammation in central nervous system (CNS). It has been reported that propofol, the most commonly used anesthetic, could inhibit inflammation response in CNS. In this study, we investigated the effects of tumor necrosis factor-α(TNF-α) and propofol on occludin expression in human cerebral microvascular endothelial cell line, D3 clone (hCMEC/D3 cells), and explored the underlying mechanisms. Methods: The hCMEC/D3 cells were treated with propofol, followed by TNF-α. The expression and phosphorylation of Hif-1α, VEGF, VEGFR-2, ERK, p38MAPK and occludin were measured by Western blot analysis. The cell viability of hCMEC/D3 cells was measured by cell counting kit-8. Results: TNF-α (10 ng/ml, 4 h) significantly decreased the expression of occludin, which was attenuated by propofol (25 μM). TNF-α induced Hif-1α/VEGF/VEGFR-2/ERK signaling pathway, while propofol could inhibit it. TNF-α induced the phosphorylation of p38MAPK, while propofol had no effect on it. In addition, the inhibitors of Hif-1α, VEGFR-2, and ERK could reduce the effect of TNF-α on occludin expression. Conclusion: TNF-α could decrease the expression of occludin via activating Hif-1α/VEGF/VEGFR-2/ERK signaling pathway, which was attenuated by propofol.

scholarly journals Επιδημιολογικοί και μοριακοί παράγοντες συσχετίσεως λοιμώξεως από ελικοβακτηρίδιο του πυλωρού και πολλαπλής σκλήρυνσης

2013 ◽  
Author(s):  
Εμμανουήλ Γαβαλάς
Keyword(s):  
Tumor Necrosis Factor ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Α ◽  
Ki 67 ◽  
Tnf Α ◽  
Ifn Γ ◽  
H Pylori ◽  
Factor Α ◽  
Necrosis Factor

Πρόσφατα δεδομένα μας, δείχνουν συσχέτιση μεταξύ ενεργού H. pylori λοιμώξεως και Πολλαπλής Σκλήρυνσης (ΠΣ) στον Ελλαδικό χώρο. Εντούτοις, υφίστανται διεθνώς, ελάχιστα και αντιφατικά δεδομένα που αφορούν την συσχέτιση H. pylori και ΠΣ, ενώ δεν υφίστανται ανάλογα δεδομένα όσον αφορά το κλινικώς μεμονωμένο σύνδρομο (ΚΜΣ). Σκοπός της παρούσης διδακτορικής διατριβής ήταν: (1) να επαληθευθεί η αρχική διαπίστωση ότι υφίσταται αυξημένη συχνότητα H. pylori λοιμώξεως σε ασθενείς με ΠΣ και να διερευνηθεί για πρώτη φορά η πιθανή συσχέτιση της με το ΚΜΣ, (2) να ελεγχθεί η απόπτωση και άλλοι παράμετροι, όπως διάσπαση του αιματοεγκεφαλικού φραγμού (ΑΕΦ) και η, τύπου «Δούρειου ίππου», οδός εισόδου μολυσμένων μονοκύτταρων στο Κεντρικό Νευρικό Σύστημα, ως πιθανοί παθογενετικοί μηχανισμοί μεταξύ H. pylori λοιμώξεως και ΠΣ/ΚΜΣ, (3) να διερευνηθεί ο ρόλος του οξειδωτικού στρες, στην παθογένεια των δύο νόσων (4) να μελετηθούν παράγοντες εμπλεκόμενοι στις δύο νόσους, όπως Ομοκυστεΐνη (Hcy), Κυανοκοβαλαμίνης (B12) και Φυλλικό οξύ (Fol), (5) να διερευνηθεί συσχέτιση μεταξύ των αναφερόμενων παθογενετικών παραγόντων και νευρολογικών παραμέτρων και (6) να διερευνηθεί γενετική επίπτωση στην εκδήλωση των δύο παθήσεων, εκτιμώντας τη συσχέτιση των HLA απλοτύπων/αλληλίων σε H. pylori (+). ασθενείς με ΠΣ/ΚΜΣ. Στην παρούσα μελέτη συμπεριλήφθηκαν συνολικά 92 ασθενείς (44 με ΠΣ, 48 με ΚΜΣ) και 20 ασθενείς με σιδηροπενική αναιμία. Η παρουσία της H. pylori λοιμώξεως διαπιστώθηκε ιστολογικώς. Στους ασθενείς, εκτιμήθηκαν: α) ανοσοϊστοχημική έκφραση ογκογονιδίων (p53, Ki-67, Bcl-2), T- (UCHL-1) και Β-λεμφοκυττάρων (BLs) (CD20), β) οι ιντερλευκίνες -1β, -2, -4, -6, -8, -10, -12, -13, η ιντερφερόνη-γ και ο tumor necrosis factor-α (TNF-α) με ELISA, γ) οι δραστικοί μεταβολίτες οξυγόνου (ROMs) με σπεκτροφωτομετρία, δ) η Hcy, η B12 και το Fol ορού με άμεση χημειοφωταύγεια, (5) οι HLA υπότυποι με τεχνικές PCR. Στην ομάδα των μαρτύρων διενεργήθη ανοσοϊστοχημεία και εκτιμήθηκαν η Hcy, η B12 και το Fol. Από την ανάλυση των ευρημάτων διαπιστώσαμε: Ι. Σημαντικά αυξημένη παρουσία ενεργού H. pylori λοιμώξεως στους ασθενείς με ΠΣ (86,4%) και ΚΜΣ (89,6%) και αποκλειστική και σημαντικά αυξημένη παρουσία ιστολογικών παραμέτρων στους H. pylori (+) ασθενείς. II. Σημαντικά αυξημένη παρουσία ανοσοϊστοχημικών παραμέτρων ασθενών έναντι μαρτύρων και H. pylori (+) ασθενών έναντι αρνητικών. III. Σημαντική αύξηση ιντερλευκινών σε H. pylori (+) ασθενείς, σε ασθενείς με παρουσία ιστολογικών και ανοσοϊστοχημικών παραμέτρων και σημαντική θετική συσχέτιση κλινικής βαρύτητας νόσου με την IFN-γ στους H. pylori (+) ασθενείς με ΚΜΣ. ΙV. Σημαντική αύξηση ROMs και σημαντική συσχέτιση με την βαρύτητα της νόσου στους H. pylori (+) ασθενείς με ΠΣ. V. Σημαντική αύξηση τιμών Hcy ασθενών έναντι μαρτύρων, σε H. pylori (+) ασθενείς, σε ασθενείς με παρουσία ιστολογικών παραμέτρων και σημαντική συσχέτιση Hcy με IgG anti-H. pylori αντισώματα VΙ. Σημαντικά συχνότερη παρουσία HLA-A26, HLA-Α30, HLA-Α32, HLA-Β49, HLA-Β57 και HLA-DR15 σε H. pylori (+) ασθενείς, σε σύγκριση με υγιείς. Τα ευρήματα αυτά δείχνουν ότι η H. pylori ενεργός λοίμωξη σε ασθενείς με ΠΣ/ΚΜΣ πιθανόν να επάγει χυμικές και κυτταρικές ανοσιακές αποκρίσεις, οι οποίες συμβάλλουν με ποικίλους μηχανισμούς, όπως διάσπαση του ΑΕΦ και μηχανισμούς τύπου «Δούρειου ίππου» και αποπτώσεως, στην παθοφυσιολογία των δύο νόσων, όπου πιθανόν εμπλέκονται γονίδια αποπτωτικά ή αντιαποπτωτικά, κυτταροκίνες, οξειδωτικό στρες, BLs, Hcy και γενετικοί παράγοντες.

scholarly journals Propofol attenuated the effect of TNF-α on occludin expression by inhibiting HIF-1α/VEGF/VEGFR-2/ERK signaling pathway in hCMEC/D3 cells

2019 ◽  
Author(s):  
Yue Zhang ◽  
Xiaowei Ding ◽  
Changhong Miao ◽  
Jiawei Chen
Keyword(s):  
Signaling Pathway ◽  
Cell Counting ◽  
Erk Signaling ◽  
Microvascular Endothelial Cell ◽  
Tight Junction Proteins ◽  
Tnf Α ◽  
Underlying Mechanisms ◽  
Factor Α ◽  
Necrosis Factor ◽  
Junction Proteins

Abstract Purpose: The levels of tight junction proteins (TJs), especially occludin, correlate with blood-brain barrier (BBB) disruption caused by inflammation in central nervous system (CNS). It has been reported that propofol, the most commonly used anesthetic, could inhibit inflammation response in CNS. In this study, we investigated the effects of tumor necrosis factor-α(TNF-α) and propofol on occludin expression in human cerebral microvascular endothelial cell line, D3 clone (hCMEC/D3 cells), and explored the underlying mechanisms. Methods: The hCMEC/D3 cells were treated with propofol, followed by TNF-α. The expression and phosphorylation of Hif-1α, VEGF, VEGFR-2, ERK, p38MAPK and occludin were measured by Western blot analysis. The cell viability of hCMEC/D3 cells was measured by cell counting kit-8. Results: TNF-α (10 ng/ml, 4 h) significantly decreased the expression of occludin, which was attenuated by propofol (25 μM). TNF-α induced Hif-1α/VEGF/VEGFR-2/ERK signaling pathway, while propofol could inhibit it. TNF-α induced the phosphorylation of p38MAPK, while propofol had no effect on it. In addition, the inhibitors of Hif-1α, VEGF, VEGFR-2, and ERK could reduce the effect of TNF-α on occludin expression. Conclusion: TNF-α could decrease the expression of occludin via activating Hif-1α/VEGF/VEGFR-2/ERK signaling pathway, which was attenuated by propofol.

Abstract 5551: Double Deficiency of Tumor Necrosis Factor-α and Interferon-γ in Bone Marrow-Derived Cells Prevents Neointimal Formation in a Murine Model of Vascular Injury

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hideki Murayama ◽  
Masafumi Takahashi ◽  
Yuji Shiba ◽  
Masaya Takamoto ◽  
Hirohiko Ise ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Vascular Injury ◽  
Tumor Necrosis ◽  
Interferon Γ ◽  
Neointimal Formation ◽  
Tnf Α ◽  
Bone Marrow Derived Cells ◽  
Ifn Γ ◽  
Factor Α ◽  
Necrosis Factor

Neointimal formation after percutaneous coronary intervention (PCI), termed restenosis, limits therapeutic revascularization. Recent evidence indicates that inflammatory responses induced by inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ), are involved in the progression of neointimal formation. However, the role of TNF-α and IFN-γ in the restenosis after PCI has not been fully understood. The purpose of this study is to examine the impact of TNF-α and IFN-γ in bone marrow-derived cells in the development of neointimal formation after vascular injury in mice. Wild-type (WT), TNF-α-deficient (TNF-α −/− ), IFN-γ-deficient (IFN-γ −/− ), and TNF-α/IFN-γ double-deficient (DKO) mice were subjected to wire-mediated vascular injury of the right femoral artery. Immunohistochemical analysis showed the expression of TNF-α and IFN-γ was detected in the neointimal lesion of WT mice, but these cytokines were not detected in the lesion of the corresponding deficient mice. Neointimal formation was significantly reduced after the injury in the DKO mice, compared to that in the WT, TNF-α −/− , and IFN-γ −/− mice (I/M ratio, WT: 2.28±0.17, TNF-α −/− : 2.13±0.20, IFN-γ −/− : 2.37±0.16, DKO: 1.32±0.10, p<0.05, each n=14–17). No significant difference in reendothelialization (CD31 staining) was observed among these groups. Further, vascular smooth muscle cell (α-SMA) and macrophage (F4/80) contents in the neointimal area also did not differ among the groups. The number of proliferating cell nuclear antigen (PCNA) and Ki-67 positive cells in the neointimal lesion was significantly decreased in DKO mice. To determine the contribution of bone marrow cells, we developed 3 types of bone marrow chimeric (BMT Wild→Wild , BMT DKO→Wild , and BMT Wild→DKO ) mice. The neointimal formation in BMT DKO→Wild mice was significantly reduced as compared to that in BMT Wild→Wild (I/M ratio, p<0.05, each n=7) and BMT Wild→DKO mice (p<0.05). These results suggest that the lack of TNF-α and IFN-γ in bone marrow-derived cells synergistically prevents neointimal formation after vascular injury and provide new insights into the mechanisms underlying the restenosis after PCI.

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