Interleukin-10 inhibits lipopolysaccharide-induced survival and extracellular signal-regulated kinase activation in human neutrophils.
Lipopolysaccharide (LPS) induces a marked delay in human neutrophil apoptosis that is reversed by the anti-inflammatory cytokine IL-10. The effect of IL-10 is specific since other agents that delay neutrophil apoptosis are not affected. To investigate mechanisms underlying the actions of IL-10, we examined signaling pathways activated by LPS per se and in response to IL-10. The MAPK kinase (MEK) 1 inhibitor PD098059, the protein kinase C (PKC) inhibitor Ro31,8220, and the phosphatidylinositol-3 kinase (PI3-K) inhibitor LY294002 all partially reversed LPS-mediated retardation of neutrophil apoptosis, but the p38 MAPK inhibitor SB203850 did not. LPS activates the transcription factor NF-kappaB, however, IL-10 did not affect the ability of LPS to activate NF-kappaB as assessed by IkappaB-alpha proteolysis. Although IL-10 did not alter activation of ERK by GM-CSF or TNF-alpha, it did inhibit activation induced by LPS. Thus our data illustrate that LPS-induced neutrophil survival is regulated by the MAPK, PKC and PI3-K pathways as well as NF-kappaB, and can be reversed by IL-10, through a mechanism involving inhibition of ERK activation. Because of the specific nature of this inhibition, we conclude that IL-10 interferes with an ERK activation pathway, which is not involved in GM-CSF or TNF-alpha signaling.
Ward
Carol
C
MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Murray
Joanna
J
Clugston
April
A
Dransfield
Ian
I
Haslett
Christopher
C
Rossi
Adriano G
AG
D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D015153:Blotting, Western; D002867:Chromones / Q000494:pharmacology; D004347:Drug Interactions; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D016753:Interleukin-10 / Q000276:immunology / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000276:immunology; D009025:Morpholines / Q000494:pharmacology; D016328:NF-kappa B / Q000276:immunology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology
D002867:Chromones; D005419:Flavonoids; D007093:Imidazoles; D007211:Indoles; D008070:Lipopolysaccharides; D009025:Morpholines; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C093394:TONSL protein, human; D016753:Interleukin-10; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C064758:Ro 31-8220