T cell–derived microvesicles induce mast cell production of IL-24: Relevance to inflammatory skin diseases - 13/06/13

Doi : 10.1016/j.jaci.2013.04.035

Irit Shefler, PhD ^a,^c, Metsada Pasmanik-Chor, PhD ^d, Dvora Kidron, MD ^b,^c, Yoseph A. Mekori, MD ^a,^c,^⁎^{∗
These authors contributed equally to this work.} , Alon Y. Hershko, MD, PhD ^a,^c,^{^{∗
These authors contributed equally to this work.}}
^a Laboratory of Allergy and Clinical Immunology, Meir General Hospital, Kfar Saba, Israel
^b Department of Pathology, Meir General Hospital, Kfar Saba, Israel
^c Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
^d Bioinformatics unit, G.S Wise Faculty of Life Science, Tel Aviv University, Tel Aviv, Israel

^∗Corresponding author: Yoseph A. Mekori, MD, Department of Medicine B, Meir Medical Center, Kfar Saba 44281, Israel.

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Abstract

Background

It has recently been shown that microvesicles derived from activated T cells can stimulate human mast cells (MCs) to degranulate and release several cytokines.

Objective

The aim of this study was to characterize microvesicle-induced MC expression patterns. Through identification of unique cytokine and chemokine expression, we attempted to reveal pathogenetic roles for this pathway of MC activation.

Methods

T cell–derived microvesicles were labeled with PKH67 to allow visualization of their interaction with human MCs. Consequent gene expression profiling was studied by using a whole-genome microarray and analyzed for identification of cellular pathway clusters. Expression of 3 selected genes, chemokine (C-C motif) ligand 3 (CCL3), chemokine (C-C motif) ligand 7 (CCL7), and IL24, was validated by means of quantitative RT-PCR and specific ELISA. IL24, which has not been recognized heretofore in MCs, was also tested for its effect on keratinocyte signal transducer and activator of transcription 3 phosphorylation and for its presence in MCs in psoriatic skin lesions.

Results

Uptake and internalization of activated T cell–derived microvesicles into human MCs occurred within 24 hours. Microvesicles induced the upregulation of several clusters of genes, notably those that are cytokine related. Among these, IL24 appeared to be a hallmark of microvesicle-induced activation. MC-derived IL-24, in turn, activates keratinocytes in vitro, as manifested by signal transducer and activator of transcription 3 (STAT3) phosphorylation, and is produced in MCs within psoriatic lesions.

Conclusion

Production of IL-24 is a unique feature of microvesicle-induced MC activation because its production by these cells has not been recognized thus far. We propose that this MC-derived cytokine might contribute to the pathologic findings in T cell–mediated skin inflammation.

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Key words : IL-24, mast cells, microvesicles, T cells

Abbreviations used : CCL3, CCL7, ERK, JNK, MAPK, MC, mvT, mvT*, STAT3

Plan

	A.Y.H. is the recipient of the Morasha program Fellowship of the Israel Science Foundation (grant no. 1084/10). This work was supported by a grant from the Israel Science Foundation (no. 1061/09 to Y.A.M.). Y.A.M. is the incumbent of the Reiss Chair in Dermatology at Tel Aviv University.
	Disclosure of potential conflict of interest: Y. A. Mekori and A. Y. Hershko have received a grant from the Israel Science Foundation. The rest of the authors declare that they have no relevant conflicts of interest.