Dataset Information

Bioactive products generated by group V sPLA(2) hydrolysis of LDL activate macrophages to secrete pro-inflammatory cytokines.

ABSTRACT:

Objective

Previous studies have established that hydrolysis of LDL by Group V secretory phospholipase A(2) (GV sPLA(2)) generates a modified particle capable of inducing macrophage foam cell formation. The aim of the present study was to determine whether GV sPLA(2)-hydrolyzed LDL (GV-LDL) produces pro-atherogenic effects in macrophages independent of cholesterol accumulation.

Methods and results

J-774 cells incubated with GV-LDL produced more TNF-alpha and IL-6 compared to cells incubated with control-LDL. Indirect immunofluorescence showed that GV-LDL but not control-LDL induced nuclear translocation of NFkappaB. Inhibitors of NFkappaB activation, effectively blocked cytokine production induced by GV-LDL. Control-LDL and GV-LDL were separated from albumin present in reaction mixtures by ultracentrifugation. The albumin fraction derived from GV-LDL contained 80% of the FFA generated and was more potent than the re-isolated GV-LDL in inducing pro-inflammatory cytokine secretion. Linoleic acid (18:2) and oleic acid (18:1) were the most abundant FFAs generated, whereas newly formed lyso-PCs contained 14:0 (myristic), 16:1 (palmitic), and 18:2 fatty acyl groups. Experiments with synthetic FFA showed that 18:1 induced J-774 cells to secrete TNF-alpha and IL-6.

Conclusions

These results indicate that in addition to promoting atherosclerotic lipid accumulation in macrophages, GV sPLA(2) hydrolysis of LDL leads to activation of NFkappaB, a key regulator of inflammation.

SUBMITTER: Boyanovsky BB

PROVIDER: S-EPMC2850046 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Publications

Bioactive products generated by group V sPLA(2) hydrolysis of LDL activate macrophages to secrete pro-inflammatory cytokines.

Boyanovsky Boris B BB Li Xia X Shridas Preetha P Sunkara Manjula M Morris Andrew J AJ Webb Nancy R NR

Cytokine 20100206 1

<h4>Objective</h4>Previous studies have established that hydrolysis of LDL by Group V secretory phospholipase A(2) (GV sPLA(2)) generates a modified particle capable of inducing macrophage foam cell formation. The aim of the present study was to determine whether GV sPLA(2)-hydrolyzed LDL (GV-LDL) produces pro-atherogenic effects in macrophages independent of cholesterol accumulation.<h4>Methods and results</h4>J-774 cells incubated with GV-LDL produced more TNF-alpha and IL-6 compared to cells ...[more]

PMID: 20138782

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Project description:Heparanase is a β-D-endoglucuronidase that cleaves heparan sulfate (HS), facilitating degradation of the extracellular matrix (ECM) and the release of HS-bound biomolecules including cytokines. The remodeling of the ECM by heparanase is important for various physiological and pathological processes, including inflammation, wound healing, tumour angiogenesis and metastasis. Although heparanase has been proposed to facilitate leukocyte migration through degradation of the ECM, its role in inflammation by regulating the expression and release of cytokines has not been fully defined. In this study, the role of heparanase in regulating the expression and release of cytokines from human and murine immune cells was examined. Human peripheral blood mononuclear cells treated ex vivo with heparanase resulted in the release of a range of pro-inflammatory cytokines including IL-1β, IL-6, IL-8, IL-10 and TNF. In addition, mouse splenocytes treated ex vivo with heparanase resulted in the release of IL-6, MCP-1 and TNF. A similar pattern of cytokine release was also observed when cells were treated with soluble HS. Furthermore, heparanase-induced cytokine release was abolished by enzymatic-inhibitors of heparanase, suggesting this process is mediated via the enzymatic release of cell surface HS fragments. As soluble HS can signal through the Toll-like receptor (TLR) pathway, heparanase may promote the upregulation of cytokines through the generation of heparanase-cleaved fragments of HS. In support of this hypothesis, mouse spleen cells lacking the key TLR adaptor molecule MyD88 demonstrated an abolition of cytokine release after heparanase stimulation. Furthermore, TLR4-deficient spleen cells showed reduced cytokine release in response to heparanase treatment, suggesting that TLR4 is involved in this response. Consistent with these observations, the pathway involved in cytokine upregulation was identified as being NF-κB-dependent. These data identify a new mechanism for heparanase in promoting the release of pro-inflammatory cytokines that is likely to be important in regulating cell migration and inflammation.

Dataset Information

Bioactive products generated by group V sPLA(2) hydrolysis of LDL activate macrophages to secrete pro-inflammatory cytokines.

Objective

Methods and results

Conclusions

Publications

Bioactive products generated by group V sPLA(2) hydrolysis of LDL activate macrophages to secrete pro-inflammatory cytokines.

Similar Datasets

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