IL10 resistant PGS2 expression in at-risk/Type 1 diabetic human monocytes.
Aberrant prostaglandin synthase 2 (PGS2/COX2) expression constitutes an antigen presenting cell (APC) dysfunction seen in monocytes of humans at risk for or with Type 1 diabetes. During endotoxin activation of PGS2 expression in healthy monocytes, granulocyte-monocyte colony stimulating factor (GM-CSF) is activated and, in turn, promotes PGS2 gene activation. GM-CSF is considered a major target the action for IL10 in its suppression of PGS2. We found that the PGS2 expression in monocytes from 47% of at-risk and diabetic humans tested were highly resistant to suppression by IL10 (maintaining > or =50% of their untreated expression), and had significantly increased GM-CSF production in vitro (1043+/-SD2798 pg/10(6)cells, subject n=35, vs 29.7+/-SD91 pg/10(6)cells, control n=20; P=0.0165). The PGS2 insensitivity to IL10 of these cells was not due to a lack of IL10 functionality or its suppression of GM-CSF. In contrast to its effects on PGS2, IL10 regulation of GM-CSF and other monocyte factors (i.e., DR, IL1beta, TNFalpha, IL12, CD54, and CD64) remained intact. These findings suggest that the inability of IL10 to properly downregulate PGS2 gene expression may contribute to its dysregulation in Type 1 diabetes.
Litherland
S A
SA
Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA. litherla@pathology.ufl.edu
Xie
T X
TX
Grebe
K M
KM
Li
Y
Y
Moldawer
L L
LL
Clare-Salzler
M J
MJ
D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D051546:Cyclooxygenase 2; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000276:immunology / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics*; D008565:Membrane Proteins; D008875:Middle Aged; D009000:Monocytes / Q000276:immunology / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics*
D007527:Isoenzymes; D008565:Membrane Proteins; D016753:Interleukin-10; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases