Lipopolysaccharide and a social stressor influence behaviour, corticosterone and cytokine levels: Divergent actions in cyclooxygenase-2 deficient mice and wild type controls

We investigated and evaluated post-irradiation survival in cyclooxygenase-2-deficient (COX-2 KO) mice. Thirty-day survival following exposure of COX-2 KO mice to a lethal dose of 8.5 Gy of γ-rays was observed to be statistically significantly lower in both males and females, as well as when the sexes were merged, in comparisons with their wild-type counterparts. These findings were related to the previous observations concerning the detrimental influence of the COX-2 genetic disruption on hematopoiesis in sublethally irradiated mice. Deteriorated post-irradiation survival of COX-2 KO mice confirmed the previously anticipated conclusion regarding negative influence of the anti-inflammatory action of COX-2 deficiency under the conditions of exposure of the animals to ionizing radiation.

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Different effects of chronic helicobactor pylori infection on parietal and ECL cells between wild type and gastrin-deficient mice

Gastroenterology ◽

10.1016/s0016-5085(01)83624-6 ◽

2001 ◽

Vol 120 (5) ◽

pp. A728-A728

Author(s):

D CHEN ◽

L FRIISHANSEN ◽

X WANG ◽

C ZHAO ◽

H WALDUM ◽

...

Keyword(s):

Wild Type ◽

Ecl Cells ◽

Helicobactor Pylori ◽

Deficient Mice

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CCR5 deficiency decreases susceptibility to experimental cerebral malaria

Blood ◽

10.1182/blood-2002-05-1493 ◽

2003 ◽

Vol 101 (11) ◽

pp. 4253-4259 ◽

Cited By ~ 82

Author(s):

Elodie Belnoue ◽

Michèle Kayibanda ◽

Jean-Christophe Deschemin ◽

Mireille Viguier ◽

Matthias Mack ◽

...

Keyword(s):

T Cells ◽

Cerebral Malaria ◽

Cd8 T Cells ◽

Cytokine Production ◽

Wild Type ◽

Experimental Cerebral Malaria ◽

Pathologic Features ◽

Th1 Cytokine ◽

The Brain ◽

Deficient Mice

Abstract Infection of susceptible mouse strains with Plasmodium berghei ANKA (PbA) is a valuable experimental model of cerebral malaria (CM). Two major pathologic features of CM are the intravascular sequestration of infected erythrocytes and leukocytes inside brain microvessels. We have recently shown that only the CD8+ T-cell subset of these brain-sequestered leukocytes is critical for progression to CM. Chemokine receptor–5 (CCR5) is an important regulator of leukocyte trafficking in the brain in response to fungal and viral infection. Therefore, we investigated whether CCR5 plays a role in the pathogenesis of experimental CM. Approximately 70% to 85% of wild-type and CCR5+/- mice infected with PbA developed CM, whereas only about 20% of PbA-infected CCR5-deficient mice exhibited the characteristic neurologic signs of CM. The brains of wild-type mice with CM showed significant increases in CCR5+ leukocytes, particularly CCR5+ CD8+ T cells, as well as increases in T-helper 1 (Th1) cytokine production. The few PbA-infected CCR5-deficient mice that developed CM exhibited a similar increase in CD8+ T cells. Significant leukocyte accumulation in the brain and Th1 cytokine production did not occur in PbA-infected CCR5-deficient mice that did not develop CM. Moreover, experiments using bone marrow (BM)–chimeric mice showed that a reduced but significant proportion of deficient mice grafted with CCR5+ BM develop CM, indicating that CCR5 expression on a radiation-resistant brain cell population is necessary for CM to occur. Taken together, these results suggest that CCR5 is an important factor in the development of experimental CM.

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Surfactant protein A reduces TLR4 and inflammatory cytokine mRNA levels in neonatal mouse ileum

Scientific Reports ◽

10.1038/s41598-021-82219-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lidan Liu ◽

Chaim Z. Aron ◽

Cullen M. Grable ◽

Adrian Robles ◽

Xiangli Liu ◽

...

Keyword(s):

Proinflammatory Cytokine ◽

Inflammatory Cytokine ◽

Protein A ◽

Surfactant Protein ◽

Surfactant Protein A ◽

Mrna Levels ◽

Wild Type ◽

Cytokine Mrna ◽

Protein Levels ◽

Cytokine Levels

AbstractLevels of intestinal toll-like receptor 4 (TLR4) impact inflammation in the neonatal gastrointestinal tract. While surfactant protein A (SP-A) is known to regulate TLR4 in the lung, it also reduces intestinal damage, TLR4 and inflammation in an experimental model of necrotizing enterocolitis (NEC) in neonatal rats. We hypothesized that SP-A-deficient (SP-A−/−) mice have increased ileal TLR4 and inflammatory cytokine levels compared to wild type mice, impacting intestinal physiology. We found that ileal TLR4 and proinflammatory cytokine levels were significantly higher in infant SP-A−/− mice compared to wild type mice. Gavage of neonatal SP-A−/− mice with purified SP-A reduced ileal TLR4 protein levels. SP-A reduced expression of TLR4 and proinflammatory cytokines in normal human intestinal epithelial cells (FHs74int), suggesting a direct effect. However, incubation of gastrointestinal cell lines with proteasome inhibitors did not abrogate the effect of SP-A on TLR4 protein levels, suggesting that proteasomal degradation is not involved. In a mouse model of experimental NEC, SP-A−/− mice were more susceptible to intestinal stress resembling NEC, while gavage with SP-A significantly decreased ileal damage, TLR4 and proinflammatory cytokine mRNA levels. Our data suggests that SP-A has an extrapulmonary role in the intestinal health of neonatal mice by modulating TLR4 and proinflammatory cytokines mRNA expression in intestinal epithelium.

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Role and Regulation of Adipokines during Zymosan-Induced Peritoneal Inflammation in Mice

Endocrinology ◽

10.1210/en.2008-0327 ◽

2008 ◽

Vol 149 (8) ◽

pp. 4080-4085 ◽

Cited By ~ 20

Author(s):

Maria Pini ◽

Melissa E. Gove ◽

Joseph A. Sennello ◽

Jantine W. P. M. van Baal ◽

Lawrence Chan ◽

...

Keyword(s):

Inflammatory Infiltrate ◽

Peritoneal Lavage ◽

Lavage Fluid ◽

Wild Type ◽

Cellular Infiltrate ◽

Peritoneal Lavage Fluid ◽

Peritoneal Inflammation ◽

Leptin Deficiency ◽

Cytokine Levels

Adipokines, cytokines mainly produced by adipocytes, are active participants in the regulation of inflammation. Administration of zymosan (ZY) was used to investigate the regulation and role of adipokines during peritonitis in mice. Injection of ZY led to a significant increase in leptin levels in both serum and peritoneal lavage fluid, whereas a differential trend in local vs. systemic levels was observed for both resistin and adiponectin. The role of leptin in ZY-induced peritonitis was investigated using leptin-deficient ob/ob mice, with and without reconstitution with exogenous leptin. Leptin deficiency was associated with delayed resolution of peritoneal inflammation induced by ZY, because ob/ob mice had a more pronounced cellular infiltrate in the peritoneum as well as higher and prolonged local and systemic levels of IL-6, TNFα, IL-10, and chemokine (C-X-C motif) ligand 2 compared with wild-type mice. Reconstitution with exogenous leptin exacerbated the inflammatory infiltrate and systemic IL-6 levels in ob/ob mice while inhibiting production of TNFα, IL-10, and chemokine (C-X-C motif) ligand 2. In contrast with the important role of leptin in regulating each aspect of ZY-induced peritonitis, adiponectin deficiency was associated only with a decreased inflammatory infiltrate, without affecting cytokine levels. These findings point to a complex role for adipokines in ZY-induced peritonitis and further emphasize the interplay between obesity and inflammation.

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Toll-like Receptor 4 Signaling in Ventilator-induced Diaphragm Atrophy

Anesthesiology ◽

10.1097/aln.0b013e3182608cc0 ◽

2012 ◽

Vol 117 (2) ◽

pp. 329-338 ◽

Cited By ~ 34

Author(s):

Willem-Jan M. Schellekens ◽

Hieronymus W. H. van Hees ◽

Michiel Vaneker ◽

Marianne Linkels ◽

P. N. Richard Dekhuijzen ◽

...

Keyword(s):

Mechanical Ventilation ◽

Caspase 3 ◽

Toll Like Receptor ◽

Wild Type ◽

Toll Like Receptor 4 ◽

Ubiquitin Proteasome Pathway ◽

Ubiquitin Proteasome ◽

Proteasome Pathway ◽

Diaphragm Atrophy ◽

Deficient Mice

Background Mechanical ventilation induces diaphragm muscle atrophy, which plays a key role in difficult weaning from mechanical ventilation. The signaling pathways involved in ventilator-induced diaphragm atrophy are poorly understood. The current study investigated the role of Toll-like receptor 4 signaling in the development of ventilator-induced diaphragm atrophy. Methods Unventilated animals were selected for control: wild-type (n = 6) and Toll-like receptor 4 deficient mice (n = 6). Mechanical ventilation (8 h): wild-type (n = 8) and Toll-like receptor 4 deficient (n = 7) mice.Myosin heavy chain content, proinflammatory cytokines, proteolytic activity of the ubiquitin-proteasome pathway, caspase-3 activity, and autophagy were measured in the diaphragm. Results Mechanical ventilation reduced myosin content by approximately 50% in diaphragms of wild-type mice (P less than 0.05). In contrast, ventilation of Toll-like receptor 4 deficient mice did not significantly affect diaphragm myosin content. Likewise, mechanical ventilation significantly increased interleukin-6 and keratinocyte-derived chemokine in the diaphragm of wild-type mice, but not in ventilated Toll-like receptor 4 deficient mice. Mechanical ventilation increased diaphragmatic muscle atrophy factor box transcription in both wild-type and Toll-like receptor 4 deficient mice. Other components of the ubiquitin-proteasome pathway and caspase-3 activity were not affected by ventilation of either wild-type mice or Toll-like receptor 4 deficient mice. Mechanical ventilation induced autophagy in diaphragms of ventilated wild-type mice, but not Toll-like receptor 4 deficient mice. Conclusion Toll-like receptor 4 signaling plays an important role in the development of ventilator-induced diaphragm atrophy, most likely through increased expression of cytokines and activation of lysosomal autophagy.

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A32 EMPAGLIFOZIN IMPROVES GASTROINTESTINAL INFLAMMATION IN A MOUSE MODEL OF COLITIS

Journal of the Canadian Association of Gastroenterology ◽

10.1093/jcag/gwab002.031 ◽

2021 ◽

Vol 4 (Supplement_1) ◽

pp. 213-215

Author(s):

K Madsen ◽

H Dang ◽

N Hotte ◽

V Mocanu ◽

M Ferdaoussi ◽

...

Keyword(s):

Animal Model ◽

Sglt2 Inhibitor ◽

Direct Effects ◽

Lipocalin 2 ◽

Wild Type ◽

Gut Inflammation ◽

Beneficial Effects ◽

Histological Score ◽

Cytokine Levels ◽

Gastrointestinal Inflammation

Abstract Background Empagliflozin (EMPA) is a highly selective sodium glucose cotransporter-2 (SGLT2) inhibitor and is increasingly being utilized as an antihyperglycemic agent in the management of type 2 diabetes. Interestingly, it has been demonstrated in human trials that EMPA treatment exerts potent cardioprotective effects by reducing cardiac inflammation independently of glycemic control. Further, EMPA has also been shown to suppress LPS-induced renal and systemic inflammation in an animal model. Based on these findings, we hypothesized that EMPA treatment may also be effective in reducing gut inflammation. Aims The aim of this study was to examine the effects of treatment with EMPA on gastrointestinal inflammation in an animal model of inflammatory bowel disease and to determine mechanistic insights regarding its direct effects on gut cytokine secretion. Methods Adult male and female IL-10-/- mice with established colitis were treated with a daily gavage of EMPA (10mg/kg; n=10) or vehicle (n=10) for 14 days. Disease activity was assessed by measurement of mouse weight, colonic weight and length, histological score, cytokine levels in colonic homogenate and lipocalin-2 levels in stool. To examine for possible direct effects of EMPA, colonic explants from wild-type (n=8) and IL-10-/- (n=8) mice were incubated with increasing doses of EMPA (0.1–5 µM) ± LPS (10µg/ml) for 2 hours and tissue levels of IL-1β and TNFα protein measured by ELISA. Results After 14 days EMPA treated IL-10-/- mice had a significant improvement in colonic inflammation as evidenced by decreased colonic weight to length ratio (p=0.019), decreased fecal lipocalin-2 (p=0.03), as well as decreased enterocyte injury (p=0.01), decreased lamina propria neutrophils (p=0.01) and decreased total histological score (p=0.006). EMPA treated mice also maintained their weight over the 14 days while untreated mice continued to lose weight (p=0.04). There were no significant differences in colonic homogenate levels of TNFα, IL-1β, or IL-6 or in blood glucose levels between EMPA-treated mice and controls. In addition, EMPA did not suppress levels of basal or LPS-induced TNFα and IL-1β in colonic explants from either wild-type or IL-10-/- mice suggesting that the beneficial effects in IL-10-/- mice were not due to direct effects of EMPA on colonic TNFα or IL-1β cytokine levels. Conclusions EMPA treatment dramatically improved histologic and fecal inflammatory markers and maintained body weight in adult IL-10-/- mice with established colitis. These findings suggest further investigations into the effects of EMPA in treating gut inflammation are warranted. Funding Agencies CAG, CIHR

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Vasomotor responses in MnSOD-deficient mice

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01215.2003 ◽

2004 ◽

Vol 287 (3) ◽

pp. H1141-H1148 ◽

Cited By ~ 25

Author(s):

Jon J. Andresen ◽

Frank M. Faraci ◽

Donald D. Heistad

Keyword(s):

Oxidative Stress ◽

Acute Hypoxia ◽

Vasomotor Response ◽

Wild Type ◽

Similar Extent ◽

Sod Activity ◽

Vasomotor Function ◽

Mitochondrial Superoxide ◽

Prostaglandin F ◽

Deficient Mice

MnSOD is the only mammalian isoform of SOD that is necessary for life. MnSOD−/− mice die soon after birth, and MnSOD+/− mice are more susceptible to oxidative stress than wild-type (WT) mice. In this study, we examined vasomotor function responses in aortas of MnSOD+/− mice under normal conditions and during oxidative stress. Under normal conditions, contractions to serotonin (5-HT) and prostaglandin F2α (PGF2α), relaxation to ACh, and superoxide levels were similar in aortas of WT and MnSOD+/− mice. The mitochondrial inhibitor antimycin A reduced contraction to PGF2α and impaired relaxation to ACh to a similar extent in aortas of WT and MnSOD+/− mice. The Cu/ZnSOD and extracellular SOD inhibitor diethyldithiocarbamate (DDC) paradoxically enhanced contraction to 5-HT and superoxide more in aortas of WT mice than in MnSOD+/− mice. DDC impaired relaxation to ACh and reduced total SOD activity similarly in aortas of both genotypes. Tiron, a scavenger of superoxide, normalized contraction to 5-HT, relaxation to ACh, and superoxide levels in DDC-treated aortas of WT and MnSOD+/− mice. Hypoxia, which reportedly increases superoxide, reduced contractions to 5-HT and PGF2α similarly in aortas of WT and MnSOD+/− mice. The vasomotor response to acute hypoxia was similar in both genotypes. In summary, under normal conditions and during acute oxidative stress, vasomotor function is similar in WT and MnSOD+/− mice. We speculate that decreased mitochondrial superoxide production may preserve nitric oxide bioavailability during oxidative stress.

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A role for CD9 molecules in T cell activation.

Journal of Experimental Medicine ◽

10.1084/jem.184.2.753 ◽

1996 ◽

Vol 184 (2) ◽

pp. 753-758 ◽

Cited By ~ 63

Author(s):

X G Tai ◽

Y Yashiro ◽

R Abe ◽

K Toyooka ◽

C R Wood ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Immune Responses ◽

T Cell Activation ◽

Cell Activation ◽

Expression Cloning ◽

Wild Type ◽

Almost All ◽

Antigen Presenting ◽

Deficient Mice

Costimulation mediated by the CD28 molecule plays an important role in optimal activation of T cells. However, CD28-deficient mice can mount effective T cell-dependent immune responses, suggesting the existence of other costimulatory systems. In a search for other costimulatory molecules on T cells, we have developed a monoclonal antibody (mAb) that can costimulate T cells in the absence of antigen-presenting cells (APC). The molecule recognized by this mAb, 9D3, was found to be expressed on almost all mature T cells and to be a protein of approximately 24 kD molecular mass. By expression cloning, this molecule was identified as CD9, 9D3 (anti-CD9) synergized with suboptimal doses of anti-CD3 mAb in inducing proliferation by virgin T cells. Costimulation was induced by independent ligation of CD3 and CD9, suggesting that colocalization of these two molecules is not required for T cell activation. The costimulation by anti-CD9 was as potent as that by anti-CD28. Moreover, anti-CD9 costimulated in a CD28-independent way because anti-CD9 equally costimulated T cells from the CD28-deficient as well as wild-type mice. Thus, these results indicate that CD9 serves as a molecule on T cells that can deliver a potent CD28-independent costimulatory signal.

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Altered V-ATPase expression in renal intercalated cells isolated from B1 subunit-deficient mice by fluorescence-activated cell sorting

AJP Renal Physiology ◽

10.1152/ajprenal.00394.2012 ◽

2013 ◽

Vol 304 (5) ◽

pp. F522-F532 ◽

Cited By ~ 21

Author(s):

Luca Vedovelli ◽

John T. Rothermel ◽

Karin E. Finberg ◽

Carsten A. Wagner ◽

Anie Azroyan ◽

...

Keyword(s):

Cell Sorting ◽

Collecting Duct ◽

Egfp Expression ◽

Intercalated Cells ◽

Wild Type ◽

Western Blots ◽

Atpase Subunit ◽

Protein Levels ◽

Baseline Conditions ◽

Deficient Mice

Unlike human patients with mutations in the 56-kDa B1 subunit isoform of the vacuolar proton-pumping ATPase (V-ATPase), B1-deficient mice (Atp6v1b1−/−) do not develop metabolic acidosis under baseline conditions. This is due to the insertion of V-ATPases containing the alternative B2 subunit isoform into the apical membrane of renal medullary collecting duct intercalated cells (ICs). We previously reported that quantitative Western blots (WBs) from whole kidneys showed similar B2 protein levels in Atp6v1b1−/− and wild-type mice (Păunescu TG, Russo LM, Da Silva N, Kovacikova J, Mohebbi N, Van Hoek AN, McKee M, Wagner CA, Breton S, Brown D. Am J Physiol Renal Physiol 293: F1915–F1926, 2007). However, WBs from renal medulla (including outer and inner medulla) membrane and cytosol fractions reveal a decrease in the levels of the ubiquitous V-ATPase E1 subunit. To compare V-ATPase expression specifically in ICs from wild-type and Atp6v1b1−/− mice, we crossed mice in which EGFP expression is driven by the B1 subunit promoter (EGFP-B1+/+ mice) with Atp6v1b1−/− mice to generate novel EGFP-B1−/− mice. We isolated pure IC populations by fluorescence-assisted cell sorting from EGFP-B1+/+ and EGFP-B1−/− mice to compare their V-ATPase subunit protein levels. We report that V-ATPase A, E1, and H subunits are all significantly downregulated in EGFP-B1−/− mice, while the B2 protein level is considerably increased in these animals. We conclude that under baseline conditions B2 upregulation compensates for the lack of B1 and is sufficient to maintain basal acid-base homeostasis, even when other V-ATPase subunits are downregulated.

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