M-CSF induces the expression of a membrane-bound form of IL-18 in a subset of human monocytes differentiating in vitro toward macrophages.
IL-18 is a proinflammatory cytokine belonging to the "IL-1 family" that has been shown to play a prominent role in the induction of type 1 immune responses. Here, we show that M-CSF induces the expression of a membrane-bound form of IL-18 (mIL-18) in a subset of human blood monocytes differentiating toward macrophages. While monocytes, DC, and GM-CSF-treated monocytes did not express mIL-18, its expression was detected in approximately 30-40% of M-CSF-primed macrophages differentiating from both CD16(-) and CD16(+) monocytes. Treatment with the caspase-1 inhibitor significantly reduced mIL-18 expression suggesting the requirement of an assembled inflammasome for IL-18 surface expression. Polarization toward M2 did not modify mIL-18 expression. On the contrary, LPS stimulation of both M0 and M2 (mIL-18(+) ) macrophages induced shedding of mIL-18, which was likely mediated by the activation of cellular protease(s). Importantly, the soluble form IL-18 (sIL-18) induced in autologous resting NK cells both the expression of CCR7 and the production of high amounts of IFN-γ, which was virtually abrogated by Ab-mediated neutralization of sIL-18. Overall our data shed new light on the cells and mechanisms leading to the release of sIL-18, the major IFN-γ-inducing factor in both physiological and pathological immune responses.
Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy.
Francesca
F
Bellora
Roberta
R
Castriconi
Andrea
A
Doni
Claudia
C
Cantoni
Lorenzo
L
Moretta
Alberto
A
Mantovani
Alessandro
A
Moretta
Cristina
C
Bottino
D020170:Caspase 1 / Q000502:physiology; D002454:Cell Differentiation; D002478:Cells, Cultured; D058851:GPI-Linked Proteins / Q000032:analysis; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D020382:Interleukin-18 / Q000032:analysis / Q000502:physiology*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D008264:Macrophages / Q000737:chemistry / Q000166:cytology*; D009000:Monocytes / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D017452:Receptors, IgG / Q000032:analysis
C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D020382:Interleukin-18; D017452:Receptors, IgG; D016173:Macrophage Colony-Stimulating Factor; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D020170:Caspase 1