Plasma tumor necrosis factor-a (TNF-a) levels in Gaucher disease

Michelakakis, Helen; Spanou, Cleopatra; Kondyli, A. P.; Dimitriou, Evangelia; Weely, Sonja van; Hollak, Carla E. M.; Oers, Marinus H. J. van; Aerts, Johannes M. F. G.

doi:10.1016/s0925-4439(96)00056-7

Cited by 81 publications

(51 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The fact that the plasma levels of IL6 and TNFa are normal does not exclude the possibility that concentrations of these cytokines in the vicinity of the Gaucher macrophages are abnormally high. In this respect, it is of interest to mention that elevated plasma levels of TNFa have been found in the more severe type 2 and 3 forms of Gaucher disease and to a lesser extent in some type 1 Gaucher disease patients (9). In another recent study no elevations in TNFa concentrations in type 1 disease could be established (10).…”

Section: Discussionmentioning

confidence: 95%

See 1 more Smart Citation

Elevated Levels of M-CSF, sCD14 and IL8 in Type 1 Gaucher Disease

Hollak

Evers

Aerts

et al. 1997

Blood Cells, Molecules, and Diseases

Self Cite

136

View full text Add to dashboard Cite

ABSTRACT:In type 1 Gaucher disease, decreased activity of glucocerebrosidase results in accumulation of glucosylceramide in macrophages. Infiltration of liver, spleen and bone marrow by lipid-laden macrophages leads to hepatosplenomegaly, bone lesions and cytopenia. These abnormal macrophages may produce and release macrophage derived factors and cytokines, which could contribute to the pathophysiology of the disease. Whether these cytokines and factors are elevated in Gaucher disease is currently unknown. In 29 type 1 Gaucher disease patients we measured serum levels of the macrophage derived cytokines IL8, IL6, TNFa , M-CSF and the monocyte/macrophage activation marker sCD14. These factors were studied in relation to disease severity and during treatment with enzyme supplementation therapy. Most patients showed remarkably elevated levels of M-CSF (2-8 fold) and sCD14 (2-5 fold) as compared to normal controls. Levels of IL8 were elevated in all patients (2-20 fold), whereas levels of IL6 and TNFa were normal. There was a significant correlation between severity of the disease as determined by the severity score index (SSI), and M-CSF, sCD14 and IL8 levels. M-CSF and sCD14 levels also correlated with the excess liver and spleen volumes. During treatment with alglucerase, levels of M-CSF and sCD14 declined, but IL8 remained unchanged. The relative reduction in excess liver and spleen volume did not correlate with the relative reduction in M-CSF or sCD14 levels. We conclude that serum levels of M-CSF, sCD14 and IL8 are increased in type 1 Gaucher disease. The biological activities of M-CSF and IL8 may add to the pathophysiology of the disease.

show abstract

Section: Discussionmentioning

confidence: 95%

“…Indeed, in vitro stimulation of murine macrophages with glucosylceramide has revealed enhanced production of IL1 (8). Recently, elevated plasma levels of TNFa were reported in some patients with Gaucher disease (9). In another study, increased levels of IL6 and IL10, but not of TNFa and IL1, were established (10).…”

Section: Introductionmentioning

confidence: 99%

Elevated Levels of M-CSF, sCD14 and IL8 in Type 1 Gaucher Disease

Hollak

Evers

Aerts

et al. 1997

Blood Cells, Molecules, and Diseases

Self Cite

136

View full text Add to dashboard Cite

show abstract

“…This lysosomal storage leads to the characteristic engorged macrophages, known as Gaucher macrophages (GMs) or ‘Gaucher cells’ (Machaczka et al ., 2011), and contributes to the organomegaly, bone disease and cytopenia typically encountered in patients with GD. Furthermore, glycolipid accumulation and lysosomal dysfunction in GD serve to prime macrophages to release pro‐inflammatory cytokines in response to stimuli (Michelakakis et al ., 1996; Allen et al ., 1997; Barak et al ., 1999). Thus, GMs provide a unique model to explore the mechanisms underlying defective erythrophagocytosis and its relationship to inflammation.…”

Section: Introductionmentioning

confidence: 99%

Lysosomal storage and impaired autophagy lead to inflammasome activation in G aucher macrophages

et al. 2015

View full text Add to dashboard Cite

SummaryGaucher disease, the inherited deficiency of lysosomal glucocerebrosidase, is characterized by the presence of glucosylcer‐amide macrophages, the accumulation of glucosylceramide in lysosomes and the secretion of inflammatory cytokines. However, the connection between this lysosomal storage and inflammation is not clear. Studying macrophages derived from peripheral monocytes from patients with type 1 Gaucher disease with genotype N370S/N370S, we confirmed an increased secretion of interleukins IL‐1β and IL‐6. In addition, we found that activation of the inflammasome, a multiprotein complex that activates caspase‐1, led to the maturation of IL‐1β in Gaucher macrophages. We show that inflammasome activation in these cells is the result of impaired autophagy. Treatment with the small‐molecule glucocerebrosidase chaperone NCGC758 reversed these defects, inducing autophagy and reducing IL‐1β secretion, confirming the role of the deficiency of lysosomal glucocerebrosidase in these processes. We found that in Gaucher macrophages elevated levels of the autophagic adaptor p62 prevented the delivery of inflammasomes to autophagosomes. This increase in p62 led to activation of p65‐NF‐kB in the nucleus, promoting the expression of inflammatory cytokines and the secretion of IL‐1β. This newly elucidated mechanism ties lysosomal dysfunction to inflammasome activation, and may contribute to the massive organomegaly, bone involvement and increased susceptibility to certain malignancies seen in Gaucher disease. Moreover, this link between lysosomal storage, impaired autophagy, and inflammation may have implications relevant to both Parkinson disease and the aging process. Defects in these basic cellular processes may also provide new therapeutic targets.

show abstract

“…It has been previously shown that Gaucher disease (GD) might be accompanied by low-grade, subclinical, and smoldering internal inflammation [1][2][3][4][5]. This low-grade inflammation might be accompanied by the appearance of enhanced concentrations of adhesive macromolecules in the peripheral blood [6].…”

Section: Introductionmentioning

confidence: 99%

Rheological determinants in patients with Gaucher disease and internal inflammation

et al. 2004

View full text Add to dashboard Cite

The purpose of this study was to determine whether the inflammatory response in patients with Gaucher disease (GD) is accompanied by enhanced adhesiveness/aggregation of both red and white blood cells. Sixty patients with GD and matched controls were included. The degree of erythrocyte and leukocyte adhesiveness/aggregation was determined by using a simple slide test and image analysis. Patients with GD had significantly elevated concentrations of fibrinogen (328 vs. 262 mg/dl, P < 0.0001) and accelerated erythrocyte sedimentation rates (27 vs. 13 mm/H, P < 0.005). This was accompanied by a significantly enhanced degree of erythrocyte (75 vs. 85, P < 0.0001) and leukocyte (3.5 vs. 1.3, P < 0.002) adhesiveness/aggregation. The low-grade, smoldering, and subclinical internal inflammation in individuals with GD is accompanied by an increased degree of erythrocyte and leukocyte adhesiveness/aggregation. These findings might have rheological consequences in terms of microcirculatory slow flow and tissue hypoxemia. Am.

show abstract

Plasma tumor necrosis factor-a (TNF-a) levels in Gaucher disease

Cited by 81 publications

References 17 publications

Elevated Levels of M-CSF, sCD14 and IL8 in Type 1 Gaucher Disease

Elevated Levels of M-CSF, sCD14 and IL8 in Type 1 Gaucher Disease

Lysosomal storage and impaired autophagy lead to inflammasome activation in G aucher macrophages

Rheological determinants in patients with Gaucher disease and internal inflammation

Contact Info

Product

Resources

About