Priming with IL-4 and IL-13 during HIV-1 infection restores in vitro IL-12 production by mononuclear cells of HIV-infected patients.
The production of proinflammatory cytokines can be regulated by several factors that exert activating or inhibitory effects. IL-4, IL-10, IL-13, TGF-beta, and PGE2 have demonstrated a very wide range of potent macrophage-deactivating activities and, specifically, down-regulation of the production of many proinflammatory monokines. IL-12 plays a key role during immune response by providing a link between natural resistance and adaptive immunity. We and others have previously shown an impairment in IL-12 production by PBMC from HIV-1-infected individuals in response to various stimuli, but defining the mechanism responsible remains elusive. In this study, we observed that pretreatment of PBMC from patients with IL-4 or IL-13 for 24 h primes the cells for enhanced production of IL-12 in response to Staphylococcus aureus, and almost completely restores their deficient IL-12 production when compared with healthy controls. Although this priming effect was completely abrogated by IL-10 and PGE2, IL-10 was produced equivalently by untreated and IL-4- or IL-13-pretreated PBMC from both patients and controls. Additionally, indomethacin, which shuts off PGE2 synthesis, and cAMP-blocking reagents failed to restore or enhance IL-12 production. The priming effect of IL-4 and IL-13 is at the transcription level for both p40 and p35 genes. This complete restoration of IL-12 production by Th2-associated cytokines was unexpected in light of the mutually antagonistic roles of IL-12 and IL-4 in promoting Th1 or Th2 immune responses.
Marshall
J D
JD
The Wistar Institute of Anatomy and Biology, Philadelphia, PA 19104, USA.
Robertson
S E
SE
Trinchieri
G
G
Chehimi
J
J
D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D016753:Interleukin-10 / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis*; D018793:Interleukin-13 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D009000:Monocytes / Q000378:metabolism*; D011458:Prostaglandins E / Q000502:physiology; D013211:Staphylococcus aureus / Q000276:immunology; D018418:Th2 Cells / Q000378:metabolism; D014158:Transcription, Genetic
D018793:Interleukin-13; D011458:Prostaglandins E; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D007213:Indomethacin