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Interactions Transcription Factor, STAT3 Immunological Trigger of Mast Cells by Monomeric IgE: Effect on Microphthalmia Transcription Factor, STAT3 Network of Interactions This information is current as of October 2, 2021. Amir Sonnenblick, Carmit Levy and Ehud Razin J Immunol 2005; 175:1450-1455; ; doi: 10.4049/jimmunol.175.3.1450 http://www.jimmunol.org/content/175/3/1450 Downloaded from References This article cites 42 articles, 23 of which you can access for free at: http://www.jimmunol.org/content/175/3/1450.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on October 2, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Immunological Trigger of Mast Cells by Monomeric IgE: Effect on Microphthalmia Transcription Factor, STAT3 Network of Interactions1 Amir Sonnenblick, Carmit Levy, and Ehud Razin2 Microphthalmia transcription factor (MITF) and STAT3 are two transcription factors that play a major role in the regulation of growth and function of mast cells and melanocytes. We have previously provided experimental evidence regarding the functional cross-talk between MITF, protein inhibitor of activated STAT3, and STAT3 in response to cytokine activation of mast cells. Recent studies have demonstrated that binding of different IgE molecules to their Fc⑀RI induces a spectrum of intracellular events in the absence of specific Ag. In this work, we show for the first time that, in mouse bone marrow-derived mast cells and in rat basophilic leukemia cells, monomeric IgE alone can induce the MITF-protein inhibitor of activated STAT3-STAT3 network of interactions and leads to phosphorylation of MITF at S73 and of STAT3 at both tyrosine 705 and S727. This phosphorylation increases the Downloaded from transcriptional activity of MITF and STAT3 as indicated by mRNA accumulation of their target genes such as Bcl-2, granzyme B, and c-Myc. Interestingly, MITF and STAT3 were not found to be obligatory factors in the anti-apoptotic response induced by IgE. Thus, the phenomenon that IgE alone was able to induce transcription factors that are essential for mast cell function could contribute to our understanding of the pathogenesis of allergy and its associated diseases. The Journal of Immunology, 2005, 175: 1450–1455. http://www.jimmunol.org/ t has been known for decades that cross-linking of IgE bound lanocytes (5). In humans, mutation in this gene causes Waarden- to mast cell high affinity Fc⑀RI with multivalent Ag initiates burg syndrome type II (6). MITF regulates the expression of I their activation by promoting Fc⑀RI aggregation. mouse mast cell protease (mMCP)-6 (7), mMCP-5 (8), c-kit (9), Studies on the survival effect of monomeric IgE showed that IgE p75 nerve growth factor (8), granzyme B (10), tryptophan hydrox- binding alone to Fc⑀RI induces the secretion of a variety of cyto- ylase (11), and others. We have previously identified two MITF- kines that enhance cell survival by an autocrine mechanism (1). interacting proteins, Hint (formerly known as protein kinase CI) This model was supported by the observation that the Akt and (12) and protein inhibitor of activated STAT3 (PIAS3) (13), using MAPK pathways could be activated by using monomeric IgE the yeast two-hybrid system with the basic helix-loop-helix leucine alone. Support for these in vitro phenomena come from in vivo zipper domain as a bait. These two MITF-associated proteins were by guest on October 2, 2021 studies that demonstrated that IgE Abs can promote immune sen- shown to be repressors of MITF transcriptional activity (12, 13). sitization to hapten in the skin, independently of Ag (2). Thus, the STAT3 is a transcription factor involved in signal transduction literature supplies us with good indications that stimulation of mast pathways that are activated by the IL-6 family of cytokines. It is cells via Fc⑀RI could be caused by binding of monomeric IgE. tyrosine phosphorylated by JAK, translocates as a dimer into the The interplay between microphthalmia transcription factor nucleus, and activates specific genes (14). STAT3 signaling has (MITF)3 and STAT3 in response to activation of mast cells by been shown to prevent programmed cell death and enhance cell monomeric IgE is the focus of the present study. proliferation through regulating genes such as Bcl-xL, Mcl-l,c- MITF is a basic helix-loop-helix leucine zipper DNA-binding Myc, and cyclin D1 (15–18). protein (3). Its gene resides at the mi locus in mice (4), and mu- PIAS3 was identified as inhibitor of both activated STAT3 (19) tation of this gene results in deafness, bone loss, small eyes, and and MITF (13). We have previously provided experimental evi- poorly pigmented eyes and skin (5). The primary cell types af- dence regarding the functional cross-talk among MITF, PIAS3, fected in MITF-deficient mice are mast cells, osteoclasts, and me- and STAT3 in response to cytokine activation of mast cells. Fur- thermore, our results suggest that STAT3 acts in an indirect man- ner as a regulatory factor of MITF transcriptional activity. We Department of Biochemistry, Hebrew University Hadassah Medical School, Jerusa- lem, Israel showed that on IL-6/IL-6R or stem cell factor (SCF) activation, PIAS3 is mobilized from MITF to the activated STAT3, due to the Received for publication February 18, 2005. Accepted for publication May 20, 2005. phosphorylation of MITF at S409 (20). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance In this work, we show that monomeric IgE alone can mediate with 18 U.S.C. Section 1734 solely to indicate this fact. the MITF-PIAS3-STAT3 network of interactions and lead to phos- 1 This work was supported by U.S. Binational Science Foundation Grant 2000016, phorylation and transcriptional activation of MITF and STAT3 Israeli Academy of Science Grant 159/00, and German-Israel Foundation Grant transcription factors. 1-726-10.2/2002. 2 Address correspondence and reprint requests to Dr. Ehud Razin, Department of Biochemistry, Hebrew University Hadassah Medical School, P.O. Box 12272, Jerusa- Materials and Methods lem 91120, Israel. E-mail address: [email protected] Mice 3 Abbreviations used in this paper: MITF, microphthalmia transcription factor; sp/sp mMCP, mouse mast cell protease; BMMC, bone marrow-derived mast cells; PIAS3, Mouse colonies were established from transgenic mice (MITF and sp/di protein inhibitor of activated STAT3; RBL, rat basophilic leukemia; wt, wild type; MITF ) kindly provided by Dr. Lynne Lamoreux (College of Veterinary SCF, stem cell factor. Medicine, Texas A&M University, College Station, TX). Mice carrying the Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 The Journal of Immunology 1451 MITF encoded by the mutant misp are unable to incorporate exon 6a into Indirect fluorescent immunocytochemistry the MITF message due to a splice site mutation (21). Failure to express exon 6a has little phenotypic effect in heterozygous or homozygous mutant RBL cells were cotransfected with GFP-PIAS3, STAT3 flag tagged, and mice. An effect is seen only when the misp mutation is in combination with MITF. Cells were grown on glass coverslips in six-well plates. After ex- another mutation at the locus. The MITFdi mutation arose in a cross be- tensive washing with PBS, the cells were fixed with 1.5 ml of 3.7% form- tween a PT female and an ethylnitrosourea-treated C3H/HeH male (22). aldehyde in PBS for 10 min. The fixed cells were then washed with PBS MITF encoded by the mutant midi allele is lacking the Zip domain (23) due and permeabilized with 1.5 ml of Triton X-100 diluted 1/2 with PBS con- toaCtoTtransition in exon 8 at position 916, which introduces a pre- taining 7.5 mg of BSA. After 45 min of blocking with normal donkey mature stop codon between the basic helix-loop-helix and the leucine zip- serum, the cells were stained with mouse anti-MITF and rabbit anti-flag per domain. Heterozygous appear normal; however, when they are com- followed by the addition of rhodamine-conjugated goat anti-mouse IgG bined with the misp mutant, the heterozygous have white coats with and Cy5-conjugated goat anti-rabbit IgG (Jackson ImmunoResearch Lab- pigmented patches, which enables us to select and breed them. All exper- oratories). Fluorescence analysis was performed using the Zeiss LSM 410 iments involving mice were reviewed and approved by our institute’s re- confocal laser scanning system connected to a Zeiss Axiovert 135M mi- view committee. croscope (Zeiss). Green fluorescence of GFP-labeled PIAS3 was excited with an argon laser (488 nm excitation line with 515 nm long pass barrier filter). Rhodamine-conjugated goat anti-mouse Ab was excited with a he- Cell culture and treatments lium-neon laser (543 nm excitation line with 570 nm long pass barrier Femoral bone marrow cells derived from mice were cultured in IL-3-con- filter). Cy5-conjugated goat anti-rabbit was simultaneously excited with a taining medium for 3 wk to generate bone marrow-derived mast cells helium-neon laser (633 nm excitation line).
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