Immunoregulation of dendritic cells by IL-10 is mediated through suppression of the PI3K/Akt pathway and of IkappaB kinase activity.
Interleukin-10 (IL-10) has potent immunoregulatory effects on the maturation and the antigen-presenting cell (APC) function of dendritic cells (DCs). The molecular basis underlying these effects in DCs, however, is ill defined. It is well established that the transcription factor NF-kappaB is a key regulator of DC development, maturation, and APC function. This study was initiated to determine the effects of IL-10 on the NF-kappaB signaling pathway in immature DCs. IL-10 pretreatment of myeloid DCs cultured from bone marrow resulted in reduced DNA binding and nuclear translocation of NF-kappaB after anti-CD40 antibody or lipopolysaccharide (LPS) stimulation. Furthermore, inhibited NF-kappaB activation was characterized by reduced degradation, phosphorylation, or both of IkappaBalpha and IkappaBepsilon but not IkappaBbeta and by reduced phosphorylation of Ser536, located in the trans-activation domain of p65. Notably, IL-10-mediated inhibition of NF-kappaB coincided with suppressed IkappaB kinase (IKK) activity in vitro. Furthermore, IL-10 blocked inducible Akt phosphorylation, and inhibitors of phosphatidylinositol 3-kinase (PI3K) effectively suppressed the activation of Akt, IKK, and NF-kappaB. These findings demonstrate that IL-10 targets IKK activation in immature DCs and that suppressing the PI3K pathway in part mediates blockade of the pathway.
Bhattacharyya
Sandip
S
Department of Microbiology and Immunology, Mary Ellen Jones Bldg, Rm 804, Campus Box 7290, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7290. rmtisch@med.unc.edu
Sen
Pradip
P
Wallet
Mark
M
Long
Brian
B
Baldwin
Albert S
AS
Tisch
Roland
R
D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D051550:I-kappa B Kinase; D007155:Immunologic Factors / Q000494:pharmacology; D016753:Interleukin-10 / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D022423:Myeloid Cells; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000187:drug effects*
D051550:I-kappa B Kinase; D007155:Immunologic Factors; D016753:Interleukin-10; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C496564:Chuk protein, mouse; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse