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And SOCS5 in a Murine Model Suppressor of Cytokine Signaling The Control of Allergic Conjunctivitis by Suppressor of Cytokine Signaling (SOCS)3 and SOCS5 in a Murine Model This information is current as Akemi Ozaki, Yoh-ichi Seki, Atsuki Fukushima and Masato of September 28, 2021. Kubo J Immunol 2005; 175:5489-5497; ; doi: 10.4049/jimmunol.175.8.5489 http://www.jimmunol.org/content/175/8/5489 Downloaded from References This article cites 40 articles, 9 of which you can access for free at: http://www.jimmunol.org/content/175/8/5489.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 September 28, 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 The Control of Allergic Conjunctivitis by Suppressor of Cytokine Signaling (SOCS)3 and SOCS5 in a Murine Model1 Akemi Ozaki,* Yoh-ichi Seki,* Atsuki Fukushima,† and Masato Kubo2* Allergic conjunctivitis (AC) is a common allergic eye disease characterized by clinical symptoms such as itchiness, conjunctival congestion, elevated Ag-specific IgE, mast cell activation, and local eosinophil infiltration. In this study we established a murine model for Ag-induced AC to understand the pathogenesis of the disease. Cell transfer experiments indicated that AC can be divided into early and late phase responses (EPR and LPR). EPR was associated with IgE responses, leading to itchiness, whereas LPR was characterized by local eosinophil infiltration. Both EPR and LPR were significantly inhibited in STAT6-deficient mice, and adoptive transfer of Th2 cells reconstituted LPR. Furthermore, SOCS3 was highly expressed at the disease site, and T cell-specific expression of SOCS3 deteriorated clinical and pathological features of AC, indicating that Th2-mediated SOCS3 expression controls the development and persistence of AC. Reduction of the expression level in SOCS3 heterozygous mice or Downloaded from inhibition of function in dominant-negative SOCS3 transgenic mice clearly reduced the severity of AC. In contrast, constitutive expression of SOCS5, a specific inhibitor of IL-4 signaling, resulted in reduced eosinophil infiltration. These results suggest that negative regulation of the Th2-mediated response by dominant-negative SOCS3 and SOCS5 could be a target for therapeutic intervention in allergic disease. The Journal of Immunology, 2005, 175: 5489–5497. 3 llergic conjunctivitis (AC) is a spectrum of disorders pathological feature of the LPR in AC. Eosinophil attraction is http://www.jimmunol.org/ ranging from acute forms of seasonal AC to chronic and reconstituted upon cell transfer from Ag-sensitized animals in the A severe sight-threatening forms, such as vernal kerato- absence of Ag-specific IgE (3–6). Th2 cytokine responses are conjunctivitis. Seasonal AC is by far the most common form, and known to be associated with many cases of allergic disorders (7, its prevalence and incidence have been increasing. The develop- 8), such as asthma and atopic dermatitis (AD), but treatment with ment of AC is characterized by topical and constitutive Ag sensi- Abs against Th2 cytokines is insufficient in human asthmatic pa- tization, and patients suffer from several inflammatory symptoms, tients (9, 10), suggesting that such allergic diseases are a complex including itching, redness, lid swelling, and chemosis. Recent disorder, in which the significance of Th2 cells remains elusive. studies have expanded the basic knowledge of the pathophysio- AC provides another example of this situation. Treatment with logical mechanisms in AC, which is now divided into early and rIL-12 enhances the inflammatory response of AC in the conjunc- by guest on September 28, 2021 late phases. The presence of Ag-specific IgE is indispensable for tiva (11); thus, the relevance of Th1 and Th2 cells to the devel- the early phase response (EPR), which is characterized by itching, opment of AC remains unclear. but not for the late phase response (LPR). The association of IgE Suppressor of cytokine signaling (SOCS) molecules act as neg- with granule-associated preformed and newly formed mediators in ative regulators of cytokine signaling and are known to be in- mast cells has been well documented in the type 1 allergic re- volved in the pathogenesis of many inflammatory diseases (12– sponse (1), and conjunctival biopsy samples from chronic AC pa- 14). The discovery of SOCS proteins has provided new insight into tients contain a significantly higher proportion of mast cells and a the cytokine regulation of Th1 and Th2 immune responses. Mem- higher level of mediators (2), providing clinical evidence that mast bers of the SOCS family have been identified due to their marked cell activation is found in the tear fluid and serum of AC patients. conserved Src homology 2 (SH2) domain and a unique conserved The mechanisms that regulate the LPR, however, are not fully motif, referred to as the SOCS box. Eight members of the SOCS understood. The attraction of eosinophils to sensitized areas is a protein family have been identified: cytokine-inducible SH2 do- main-containing protein and SOCS1 to -7. SOCS3 has been char- *Laboratory for Signal Network, Research Center for Allergy and Immunology, acterized as a protein related to cytokine-inducible SH2 domain- RIKEN Yokohama Institute, Kanagawa, Japan; and †Department of Ophthalmology, containing protein 1 and SOCS1, and the expression of SOCS3 is Kochi Medical School, Kochi, Japan transiently induced in a variety of immune and inflammatory sit- Received for publication March 15, 2005. Accepted for publication July 22, 2005. uations by a wide variety of cytokines, including IFN-␥, IL-2, The costs of publication of this article were defrayed in part by the payment of page IL-3, IL-4, IL-6, and IL-10, as well as by pathogen-associated charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. molecular patterns. At an inflammatory site, SOCS3 works as a 1 This work was supported by a Grant in Aid for Scientific Research and a Grant in proinflammatory mediator by suppressing IL-6 signaling via Aid for Scientific Research on Priority Areas of the Ministry of Education, Culture, gp130 (15). SOCS3 is induced by IL-6 as well as by IL-10 in Sports, Science, and Technology (Japan). Y.S. is a research fellow of the Japan macrophages through STAT3 activation and preferentially inhibits Society for the Promotion of Science. the IL-6-mediated signaling pathway (16). However, SOCS3 has 2 Address correspondence and reprint requests to Dr. Masato Kubo, Laboratory for Signal Network, Research Center for Allergy and Immunology, RIKEN Yokohama distinct targets and functions in T cells. We have demonstrated a Institute, Suehiro-cho 1-7-22, Tsurumi, Yokohama, Kanagawa 230-0045, Japan. correlation between SOCS3 expression and Th2-mediated allergic E-mail address: [email protected] disease in both mice and humans (17). SOCS3 is highly expressed 3 Abbreviations used in this paper: AC, allergic conjunctivitis; AD, atopic dermatitis; in peripheral T cells from human patients with Th2 type diseases dn, dominant negative; EPR, early phase response; LPR, late phase responses; RW, ragweed pollen; SH2, Src homology 2; SOCS, suppressor of cytokine signaling; Tg, such as atopic asthma and dermatitis, and its expression tightly transgenic. correlates with the severity of disease. Serum IgE concentrations Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 5490 CONTROL OF AC BY SOCS are also increased in patients with high SOCS3 expression. In T ness, tearing, discharge, and scratching behavior, based on the criteria de- cells, SOCS3 is selectively induced under Th2 culture conditions scribed in Table I. Clinical appearance and photographs were evaluated by in the presence of IL-4. The induced SOCS3 specifically binds to two blinded observers, one of whom was an experienced ophthalmologist. ␤ Scratching behavior was monitored for 30 s, and the frequency of scratch- the cytoplasmic region of IL-12R and inhibits IL-12-mediated ing was counted and evaluated as follows: one to three times, mild; four to STAT4 activation. Such SOCS3-mediated Th1 inhibition subse- six times, moderate; and more than seven times, severe. The final score was quently enhances Th2 development and increases the incidence of calculated as the sum of both eyes in each mouse. After 24 h, eyes were allergic airway hyper-responsiveness. collected for histological analysis, and infiltrating cell number was counted in the conjunctiva. SOCS5 is highly expressed in lymphoid organs such as spleen, lymph nodes, thymus, and bone marrow in human tissue. We Experimental AC by adoptive transfer found that SOCS5 is a potential regulator of IL-4 signaling through Spleens were harvested from RW-immunized donor animals. These RW- an SH2 domain-independent interaction between the IL-4R primed splenocytes were stimulated in vitro with soluble RW extract (25 ␣-chain and SOCS5, and forced expression of SOCS5 in T cells ␮g/ml; LSL). After 3 days of stimulation, CD4ϩ T cells were enriched clearly blocks Th2 differentiation (18), indicating that SOCS5 is a using a MACS separation column (Miltenyi Biotec). Five million cells negative regulator for Th2-mediated allergic responses. However, were i.v. transferred into naive syngeneic recipient mice.
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