IL-4-dependent CD86 expression requires JAK/STAT6 activation and is negatively regulated by PKCdelta.
CD86 expression is up-regulated in activated monocytes and macrophages by a mechanism that is not clearly defined. Here, we report that IL-4-dependent CD86 expression requires activation of ERK1/2 and JAK/STAT6 but is negatively regulated by PKCdelta. PMA differentiated U937 monocytic cells when stimulated with IL-4 increased CD11b and CD86 expression by 52- and 98-fold, respectively. PMA+IL-4 treatment also induced a synergistic enhancement of ERK1/2 activation when compared to the effects of PMA and IL-4 alone. Use of the mitogen or extracellular kinase (MEK) inhibitor, PD98059, completely blocked up-regulation of CD11b and CD86 demonstrating the importance of MEK-activated ERK1/2. JAK inhibition with WHI-P154-abrogated IL-4-dependent CD11b and CD86 up-regulation and inhibited STAT6 tyrosine phosphorylation. Importantly, CD11b and CD86 expression were not reliant on IL-4-dependent activation of phosphatidylinositol 3'-kinase (PI 3-kinase). Blockade of PKCdelta activation with rottlerin prevented CD11b expression but lead to a 75- and 213-fold increase in PMA and PMA+IL-4-dependent CD86 expression, respectively. As anticipated, increasing PKCdelta activity with anti-sense reduction of CD45 increased CD11b expression and reduced CD86 expression. Likewise, rottlerin prevented nuclear localization of activated PKCdelta. We conclude from these data that IL-4-dependent CD11b expression relies predominantly on enhanced activation of ERK1/2, while IL-4-dependent CD86 expression utilizes the JAK/STAT6 pathway.
Deszo
Eric L
EL
Department of Animal Sciences, College of Agriculture, Consumer and Environmental Sciences, 1207 West Gregory Dr., University of Illinois at Urbana Champaign, Urbana, IL 61801, USA.
Brake
Danett K
DK
Kelley
Keith W
KW
Freund
Gregory G
GG
D000098:Acetophenones / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D051940:B7-2 Antigen; D001578:Benzopyrans / Q000494:pharmacology; D039481:CD11b Antigen / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D004789:Enzyme Activation; D004791:Enzyme Inhibitors; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases; D009000:Monocytes / Q000166:cytology* / Q000378:metabolism; D010703:Phorbol Esters; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051745:Protein Kinase C-delta; D011799:Quinazolines / Q000494:pharmacology
D000098:Acetophenones; D015703:Antigens, CD; D051940:B7-2 Antigen; D001578:Benzopyrans; D039481:CD11b Antigen; D004791:Enzyme Inhibitors; D005419:Flavonoids; D015847:Interleukin-4; D008562:Membrane Glycoproteins; D020928:Mitogen-Activated Protein Kinases; D010703:Phorbol Esters; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D011799:Quinazolines; C497964:CD86 protein, human; C113888:WHI P154; C032974:12-O-retinoylphorbol-13-acetate; C085746:rottlerin; C497258:PRKCD protein, human; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one