M-CSF induces the expression of a membrane-bound form of IL-18 in a subset of human monocytes differentiating in vitro toward macrophages

Authors

  • Francesca Bellora,

    1. Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy
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  • Roberta Castriconi,

    1. Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy
    2. Centro di Eccellenza per le Ricerche Biomediche, Università degli Studi di Genova, Genova, Italy
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  • Andrea Doni,

    1. Istituto Clinico Humanitas IRCCS, Rozzano, Milano, Italy
    2. Dipartimento di Medicina Traslazionale, Università degli Studi di Milano, Milano, Italy
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  • Claudia Cantoni,

    1. Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy
    2. Centro di Eccellenza per le Ricerche Biomediche, Università degli Studi di Genova, Genova, Italy
    3. Istituto Giannina Gaslini, Genova, Italy
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  • Lorenzo Moretta,

    1. Istituto Giannina Gaslini, Genova, Italy
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  • Alberto Mantovani,

    1. Istituto Clinico Humanitas IRCCS, Rozzano, Milano, Italy
    2. Dipartimento di Medicina Traslazionale, Università degli Studi di Milano, Milano, Italy
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  • Alessandro Moretta,

    1. Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy
    2. Centro di Eccellenza per le Ricerche Biomediche, Università degli Studi di Genova, Genova, Italy
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    • These authors contributed equally to this study.

  • Cristina Bottino

    Corresponding author
    1. Istituto Giannina Gaslini, Genova, Italy
    • Dipartimento di Medicina Sperimentale, Università degli Studi di Genova, Genova, Italy
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    • These authors contributed equally to this study.


Full Correspondence: Dr. Cristina Bottino, Instituto Giannina Gaslini, L. go G. Gaslini 5, 16147 Genova, Italy

Fax: +39-010-3537576

e-mail: Cristina.Bottino@unige.it

See accompanying Commentary:

http://dx.doi.org/10.1002/eji.201142635

Abstract

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-CSFinduces 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.

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