The sesquiterpene lactone parthenolide inhibits LPS- but not TNF-alpha-induced maturation of human monocyte-derived dendritic cells by inhibition of the p38 mitogen-activated protein kinase pathway.
BACKGROUND
Dendritic cells (DCs) are the most potent antigen-presenting cells, and the manipulation of DC maturation provides a strategy for the treatment of allergic and inflammatory diseases.


OBJECTIVE
In this study we examined the effect of the anti-inflammatory sesquiterpene lactone parthenolide (PTL) on DC maturation induced by LPS or TNF-alpha.


METHODS
Human monocyte-derived DCs generated by means of culture with GM-CSF and IL-4 were pretreated with PTL and subsequently stimulated with LPS or TNF-alpha.


RESULTS
PTL inhibited the upregulation of CD80, CD83, CD86, CD40, and MHC class II; the allostimulatory function; the production of TNF-alpha and IL-12; and the downregulation of FITC-labeled dextran uptake in human monocyte-derived DCs stimulated with LPS but not with TNF-alpha. The inhibitory effect of PTL on DC maturation was preceded by inhibition of the phosphorylation of p38 mitogen-activated protein kinase but not the nuclear translocation of NF-kappaB.


CONCLUSIONS
These results might offer PTL not only as a promising compound for the treatment of LPS-induced disorders, including sepsis or septic shock, by inhibition of excessive DC maturation but also as a tool to further dissect the signaling pathways involved in DC maturation.
Uchi
Hiroshi
H
Division of Immunology and Allergology, University of Geneva, Geneva, Switzerland.
Arrighi
Jean-François
JF
Aubry
Jean-Pierre
JP
Furue
Masutaka
M
Hauser
Conrad
C
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D015703:Antigens, CD / Q000096:biosynthesis; D018949:Antigens, CD1 / Q000096:biosynthesis; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen; D001692:Biological Transport; D019013:CD40 Antigens / Q000096:biosynthesis; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015536:Down-Regulation; D004705:Endocytosis / Q000187:drug effects; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007136:Immunoglobulins / Q000096:biosynthesis; D018664:Interleukin-12 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D020935:MAP Kinase Signaling System; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases; D000097802:CD83 Antigen
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015703:Antigens, CD; D018949:Antigens, CD1; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D019013:CD40 Antigens; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000949:Histocompatibility Antigens Class II; D020672:I-kappa B Proteins; D007136:Immunoglobulins; D018664:Interleukin-12; D008070:Lipopolysaccharides; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D008562:Membrane Glycoproteins; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D011505:Protein-Tyrosine Kinases; D012717:Sesquiterpenes; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000097802:CD83 Antigen; C419393:CD1a antigen; C497964:CD86 protein, human; C002669:parthenolide; C482530:MAP2K3 protein, human; C482566:MAP2K6 protein, human