Marked upregulation of cholesterol 25-hydroxylase expression by lipopolysaccharide

Ulf Diczfalusy^*, Katarina E. Olofsson, Ann-Margreth Carlsson, Mei Gong, Douglas T. Golenbock, Olav Rooyackers^**, Urban Fläring and Harry Björkbacka¹^,

^* Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden
Department of Clinical Sciences, Malmö University Hospital, Lund University, Sweden
Department of Medicine, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA
^** Department of Anesthesia and Intensive Care, Karolinska University Hospital, Stockholm, Sweden
Department of Pediatric Anaesthesia and Intensive Care, Karolinska University Hospital, Stockholm, Sweden

¹ To whom correspondence should be addressed. e-mail: harry.bjorkbacka{at}med.lu.se

During screening of genes upregulated by lipopolysaccharide(LPS; endotoxin) treatment of bone marrow-derived mouse macrophages,it was unexpectedly found that cholesterol 25-hydroxylase (Ch25h)was strongly upregulated. Treatment of macrophages with 10 ng/mlof LPS for 2 h resulted in a 35-fold increase in the expressionof Ch25h. In contrast, LPS treatment did not increase the expressionof Cyp27a1 or Cyp7b1. The increased Ch25h expression was foundto be independent of Myeloid differentiation protein 88 signalingbut dependent on Toll-like receptor 4 signaling. LPS treatmentof macrophages caused a 6- to 7-fold increase in cellular 25-hydroxycholesterolconcentration. When macrophages were treated with increasingconcentrations of 25-hydroxycholesterol, a dose-dependent releaseof CCL5 into the culture medium was observed. Intravenous injectionof LPS in eight healthy volunteers resulted in an increase inplasma 25-hydroxycholesterol concentration. The possibilityis discussed that 25-hydroxycholesterol may have a role in theinflammatory response, in addition to its more established rolein the regulation of cholesterol homeostasis.

Supplementary key words 25-hydroxycholesterol • oxysterols • endotoxin • inflammation • sepsis • macrophages

Abbreviations: CCL5, Chemokine (C-C motif) ligand 5; Ch25h, cholesterol 25-hydroxylase; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL, interleukin; LXR, liver X receptor; LPS, lipopolysaccharide; MyD88, Myeloid differentiation protein 88; TLR4, Toll-like receptor 4

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