Preformed membrane-associated stores of interleukin (IL)-12 are a previously unrecognized source of bioactive IL-12 that is mobilized within minutes of contact with an intracellular parasite.
The prevailing paradigm is that production of the interleukin (IL)-12 p70 heterodimer, a critical T helper cell type 1 (Th1)-inducing cytokine, depends on the induced transcription of the p40 subunit. Concordant with this paradigm, we found that dendritic cells (DCs) produced IL-12 p70 only after at least 2-4 h of stimulation with lipopolysaccharide plus interferon gamma. However, using several complementary experimental approaches, including electron and confocal microscopy, we now show that resting murine and human myeloid cells, including macrophages/DCs and DC-rich tissues, contain a novel source of bioactive IL-12 that is preformed and membrane associated. These preformed, membrane-associated IL-12 p70 stores are released within minutes after in vitro or in vivo contact with Leishmania donovani, an intracellular pathogen. Our findings highlight a novel source of bioactive IL-12 that is readily available for the rapid initiation of Th1 host responses to pathogens such as Leishmania species.
Quinones
M
M
South Texas Veterans Health Care System, Audie L. Murphy Division, University of Texas Health Science Center at San Antonio, Texas 78229-3900, USA.
Ahuja
S K
SK
Melby
P C
PC
Pate
L
L
Reddick
R L
RL
Ahuja
S S
SS
D000818:Animals; D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism / Q000648:ultrastructure; D002469:Cell Separation; D002478:Cells, Cultured; D015638:Cytochalasin D / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000378:metabolism* / Q000469:parasitology / Q000648:ultrastructure; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D018664:Interleukin-12 / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D007893:Leishmania donovani / Q000276:immunology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages / Q000378:metabolism* / Q000469:parasitology; D051379:Mice; D018613:Microscopy, Confocal
D008070:Lipopolysaccharides; D018664:Interleukin-12; D015638:Cytochalasin D; D007371:Interferon-gamma