Lipopolysaccharide‐induced cytokine and receptor expression and neutrophil infiltration in the liver of osteopetrosis (<i>op/op</i>) mutant mice

Jiang, Shuying; Naito, Makoto; Kaizu, Chikako; Kuwata, Kazuhisa; Hasegawa, Go; Mukaida, Naofumi; Shultz, Leonard D.

doi:10.1034/j.1600-0676.2000.020006465.x

Cited by 15 publications

(11 citation statements)

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“…The inactivity of GW2580 with regard to the above-mentioned changes could be due to its minimal impact on acute inflammation. GW2580 did not affect the 7-fold increase in blood neutrophils caused by adjuvant arthritis, a finding consistent with near normal neutrophil infiltration of the liver after LPS or bacterial challenge in CSF-1-deficient mice (Jiang et al, 2000;Guleria and Pollard, 2001). If inhibition of CSF-1 signaling has only a modest effect on neutrophil and T-cell activation (WiktorJedrzejczak et al, 1992a;Chang et al, 1995;Guleria and Pollard, 2001) one might expect GW2580 to have little influence on the changes in adjuvant arthritis driven by acute inflammation.…”

Section: Downloaded Frommentioning

confidence: 61%

Effects of the cFMS Kinase Inhibitor 5-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine (GW2580) in Normal and Arthritic Rats

Conway

Pink²,

Bergquist³

et al. 2008

J Pharmacol Exp Ther

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The cFMS (cellular homolog of the V-FMS oncogene product of the Susan McDonough strain of feline sarcoma virus) (Proc Natl Acad Sci U S A 83:3331-3335, 1986) kinase inhibitor 5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine (GW2580) inhibits colony-stimulating factor (CSF)-1-induced monocyte growth and bone degradation in vitro and inhibits CSF-1 signaling through cFMS kinase in 4-day models in mice (Proc Natl Acad Sci U S A 102:16078, 2005). In the present study, the kinase selectivity of GW2580 was further characterized, and the effects of chronic treatment were evaluated in normal and arthritic rats. GW2580 selectively inhibited cFMS kinase compared with 186 other kinases in vitro and completely inhibited CSF-1-induced growth of rat monocytes, with an IC 50 value of 0.2 M. GW2580 dosed orally at 25 and 75 mg/kg 1 and 5 h before the injection of lipopolysaccharide inhibited tumor necrosis factor-␣ production by 60 to 85%, indicating a duration of action of at least 5 h. In a 21-day adjuvant arthritis model, GW2580 dosed twice a day (b.i.d.) from days 0 to 21, 7 to 21, or 14 to 21 inhibited joint connective tissue and bone destruction as assessed by radiology, histology and bone mineral content measurements. In contrast, GW2580 did not affect ankle swelling in the adjuvant model nor did it affect ankle swelling in a model where local arthritis is reactivated by peptidoglycan polysaccharide polymers. GW2580 administered to normal rats for 21 days showed no effects on tissue histology and only modest changes in serum clinical chemistry and blood hematology. In conclusion, GW2580 was effective in preserving joint integrity in the adjuvant arthritis model while showing minimal effects in normal rats.CSF-1 promotes the survival, proliferation, and differentiation of mononuclear phagocyte lineages and regulates the response of these lineages to inflammatory challenge. CSF-1 binding to its cell surface receptor triggers autophosphorylation by receptor cFMS (cellular homolog of the V-FMS oncogene product of the Susan McDonough strain of feline sarcoma virus) (Sacca et al., 1986) kinase and a cascade of cell signaling. cFMS kinase is the cellular homolog of the v-FMS oncogene product of the Susan McDonough strain of the feline sarcoma virus (Sacca et al., 1986). The ability of CSF-1 to promote the survival, proliferation, and differentiation of bone progenitor cells, monocytes, macrophages, and osteoclasts in vitro correlates with the expression of CSF-1 receptor in these cells (for review, see Chitu and Stanley, 2006). Mice without CSF-1 (Wiktor-Jedrzejczak et al., 1990, 1992b or its receptor (Dai et al., 2002) are osteopetrotic, deficient in several macrophage populations, show decreased TNF pro-

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Section: Downloaded Frommentioning

confidence: 61%

Effects of the cFMS Kinase Inhibitor 5-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine (GW2580) in Normal and Arthritic Rats

Conway

Pink²,

Bergquist³

et al. 2008

J Pharmacol Exp Ther

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“…This strain has been characterized by a number of investigators over the last 15 years (8,12,34,35,41,46,47). Labeled "osteopetrotic" due to their low number of osteoclasts, this murine strain has been shown to have defective differentiation of monocytes into osteoclasts and mature macrophage that exhibit reduced cytokine/chemokine expression (18).…”

Section: Discussionmentioning

confidence: 99%

Role of alveolar macrophage and migrating neutrophils in hemorrhage-induced priming for ALI subsequent to septic challenge

Lomas-Neira¹,

Chung²,

Perl³

et al. 2006

American Journal of Physiology-Lung Cellular and Molecular Phys

128

127

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Acute lung injury (ALI) is identified with the targeting/sequestration of polymorphonuclear leukocytes (PMN) to the lung. Instrumental to PMN targeting are chemokines [e.g., macrophage inflammatory protein-2 (MIP-2), keratinocyte-derived chemokine (KC), etc.] produced by macrophage, PMN, and other resident pulmonary cells. However, the relative contribution of resident pulmonary macrophages as opposed to PMN in inducing ALI is poorly understood. We therefore hypothesize that depletion of peripheral blood PMN and/or the oblation of a macrophage-mediated PMN chemokine signal (via macrophage deficiency) will reduce the inflammation and ALI observed in mice following hemorrhage (Hem) and subsequent sepsis (CLP) in our murine model of ALI. To examine this we pretreated mice with either 500 microg anti-mouse Gr1 antibody/animal (to deplete PMN) or subjected mice deficient in mature macrophage (B6C3Fe-a/a-CsF1op) to Hem (90 min at 35 +/- 5 mmHg) followed by resuscitation. Twenty-four hours post-Hem, mice were subjected to CLP and killed 24 h later, and lung tissue samples were collected. Our data showed that in the absence of either peripheral blood PMN or mature tissue macrophages there was a suppression of IL-6, KC, and MIP-2 levels in lung tissue from Hem/CLP mice as well as a reduction in PMN influx to the lung and lung injury (bronchoalveolar lavage fluid protein). In contrast, lung tissue IL-10 and TNF-alpha levels were suppressed in the macrophage-deficient Hem/CLP mice compared with PMN-depleted Hem/CLP mice. Together, these data suggest that both the PMN and the macrophage are required to induce inflammation seen here, however, macrophage not PMN regulate the release of IL-10, independent of local changes in TNF.

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“…In fact, recent studies suggest that at least 2 populations of macrophage exist, and the tissue macrophages are noninflammatory cells, unlikely to be responsible for the inflammatory response (20,21). Indeed, macrophage-deficient mice have impairments in growth but retain inflammatory responses to TLR ligands (7,8). Mast cells have also received some attention as sentinel cells, as they have pre-stored TNF-α, histamine, and other mediators that can be rapidly mobilized upon activation (22).…”

Section: Discussionmentioning

confidence: 99%

“…Robust responses (cytokine production) are generated in these model systems in vitro, and similar exuberant responses are also elicited in vivo. However, macrophage-deficient mice have robust neutrophil responses to both TLR4 and TLR2 ligands (7,8), suggesting that other cell types can contribute in a meaningful way to the inflammatory cascade. In this regard, most leukocytes, platelets, and non-bone marrow-derived parenchymal cells (epithelium, endothelium, etc.)…”

Section: Introductionmentioning

confidence: 99%

Mice that exclusively express TLR4 on endothelial cells can efficiently clear a lethal systemic Gram-negative bacterial infection

Andonegui¹,

Zhou²,

Bullard³

et al. 2009

J. Clin. Invest.

112

107

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Recognition of LPS by TLR4 on immune sentinel cells such as macrophages is thought to be key to the recruitment of neutrophils to sites of infection with Gram-negative bacteria. To explore whether endothelial TLR4 plays a role in this process, we engineered and imaged mice that expressed TLR4 exclusively on endothelium (known herein as Endothelium TLR4 mice). Local administration of LPS into tissue induced comparable neutrophil recruitment in Endothelium TLR4 and wild-type mice. Following systemic LPS or intraperitoneal E. coli administration, most neutrophils were sequestered in the lungs of wild-type mice and did not accumulate at primary sites of infection. In contrast, Endothelium TLR4 mice showed reduced pulmonary capillary neutrophil sequestration over the first 24 hours; as a result, they mobilized neutrophils to primary sites of infection, cleared bacteria, and resisted a dose of E. coli that killed 50% of wild-type mice in the first 48 hours. In fact, the only defect we detected in Endothelium TLR4 mice was a failure to accumulate neutrophils in the lungs following intratracheal administration of LPS; this response required TLR4 on bone marrow-derived immune cells. Therefore, endothelial TLR4 functions as the primary intravascular sentinel system for detection of bacteria, whereas bone marrow-derived immune cells are critical for pathogen detection at barrier sites. Nonendothelial TLR4 contributes to failure to accumulate neutrophils at primary infection sites in a disseminated systemic infection.

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Lipopolysaccharide‐induced cytokine and receptor expression and neutrophil infiltration in the liver of osteopetrosis (op/op) mutant mice

Cited by 15 publications

References 0 publications

Effects of the cFMS Kinase Inhibitor 5-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine (GW2580) in Normal and Arthritic Rats

Effects of the cFMS Kinase Inhibitor 5-(3-Methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine (GW2580) in Normal and Arthritic Rats

Role of alveolar macrophage and migrating neutrophils in hemorrhage-induced priming for ALI subsequent to septic challenge

Mice that exclusively express TLR4 on endothelial cells can efficiently clear a lethal systemic Gram-negative bacterial infection

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