Major role of HSP70 as a paracrine inducer of cytokine production in human oxidized LDL treated macrophages.
Lipid accumulation and inflammation are key hallmarks of the atherosclerotic plaque and macrophage uptake of oxidized low-density lipoprotein (oxLDL) is believed to drive these processes. Initial experiments show that supernatants from oxLDL treated macrophages could induce IL-1beta production in naïve macrophages. To search for potential paracrine mediators that could mediate this effect a DNA microarray scan of oxLDL treated human macrophages was performed. This analysis revealed that oxLDL induced activation of heat shock protein (HSP) expression. HSPs have been implicated in the development of atherosclerosis, but the exact mechanisms for this is unclear. Extracellular heat shock protein 70 (HSP70) has been shown to elicit a pro-inflammatory cytokine response in monocytes and could therefore be a potential paracrine pro-inflammatory mediator. After 24 h of oxLDL treatment there was a significant increase of HSP70 concentrations in supernatants from oxLDL treated macrophages (oxLDLsup) compared to untreated controls (P<0.05). OxLDLsup could induce both interleukin (IL)-1beta and IL-12 secretion in naïve macrophages. We also demonstrate that the effect of oxLDLsup on cytokine production and release could be blocked by inhibition of HSP70 transcription or secretion or by the use of HSP70 neutralizing antibodies. This suggests that extracellular HSP70 can mediate pro-inflammatory changes in macrophages in response to oxLDL.
Research Centre for Endocrinology and Metabolism, Division of Body Composition and Metabolism, Department of Internal Medicine, Vita straket 12, Sahlgrenska Academy, Göteborg University, S-413 45 Göteborg, Sweden. Per-Arne.Svensson@medic.gu.se
Per-Arne
PA
Svensson
Alexzander
A
Asea
Mikael C O
MC
Englund
Maria A
MA
Bausero
Margareta
M
Jernås
Olov
O
Wiklund
Bertil G
BG
Ohlsson
Lena M S
LM
Carlsson
Björn
B
Carlsson
D004247:DNA / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D045604:Extracellular Fluid / Q000378:metabolism; D005434:Flow Cytometry; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis*; D007424:Intracellular Fluid / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009154:Mutation; D010084:Oxidation-Reduction; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018840:HSP70 Heat-Shock Proteins; D007375:Interleukin-1; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D004247:DNA