T cell-derived microvesicles induce mast cell production of IL-24: relevance to inflammatory skin diseases

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.

Keywords: CCL3; CCL7; Chemokine (C-C motif) ligand 3; Chemokine (C-C motif) ligand 7; ERK; Extracellular signal-regulated kinase; IL-24; JNK; Jun N-terminal kinase; MAPK; MC; Mast cell; Microvesicles derived from activated T cells; Microvesicles derived from resting T cells; Mitogen-activated protein kinase; STAT3; Signal transducer and activator of transcription 3; T cells; mast cells; microvesicles; mvT; mvT*.