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Statins can suppress DC-mediated Th2 responses through the repression of OX40-ligand and CCL17 expression.
Eur J Immunol. 2019 11; 49(11):2051-2062.EJ

Abstract

DCs and epithelial cell-derived thymic stromal lymphopoietin (TSLP) have pivotal roles in allergic inflammation. TSLP stimulates myeloid DCs to express OX40-ligand (OX40L) and CCL17, which trigger and maintain Th2 cell responses. We have previously shown that statins, which are HMG-CoA reductase inhibitors, have the ability to suppress type I IFN production by plasmacytoid DCs. Here, we extended our previous work to examine the immunomodulatory effect of statins on allergic responses, particularly the TSLP-dependent Th2 pathway induced by myeloid DCs. We found that treatment of TSLP-stimulated DCs with either pitavastatin or simvastatin suppressed both the DC-mediated inflammatory Th2 cell differentiation and CRTH2+ CD4+ memory Th2 cell expansion and also repressed the expressions of OX40L and CCL17 by DCs. These inhibitory effects of statins were mimicked by treatment with either a geranylgeranyl-transferase inhibitor or Rho-kinase inhibitor and were counteracted by the addition of mevalonate, suggesting that statins induce geranylgeranylated Rho inactivation through a mevalonate-dependent pathway. We also found that statins inhibited the expressions of phosphorylated STA6 and NF-κB-p50 in TSLP-stimulated DCs. This study identified a specific ability of statins to control DC-mediated Th2 responses, suggesting their therapeutic potential for treating allergic diseases.

Authors+Show Affiliations

First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, 573-1191, Japan.First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, 573-1191, Japan.First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, 573-1191, Japan.First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, 573-1191, Japan.First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, 573-1191, Japan.First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, 573-1191, Japan.First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, 573-1191, Japan.First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, 573-1191, Japan.First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, 573-1191, Japan.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31269241

Citation

Inagaki-Katashiba, Noriko, et al. "Statins Can Suppress DC-mediated Th2 Responses Through the Repression of OX40-ligand and CCL17 Expression." European Journal of Immunology, vol. 49, no. 11, 2019, pp. 2051-2062.
Inagaki-Katashiba N, Ito T, Inaba M, et al. Statins can suppress DC-mediated Th2 responses through the repression of OX40-ligand and CCL17 expression. Eur J Immunol. 2019;49(11):2051-2062.
Inagaki-Katashiba, N., Ito, T., Inaba, M., Azuma, Y., Tanaka, A., Phan, V., Kibata, K., Satake, A., & Nomura, S. (2019). Statins can suppress DC-mediated Th2 responses through the repression of OX40-ligand and CCL17 expression. European Journal of Immunology, 49(11), 2051-2062. https://doi.org/10.1002/eji.201847992
Inagaki-Katashiba N, et al. Statins Can Suppress DC-mediated Th2 Responses Through the Repression of OX40-ligand and CCL17 Expression. Eur J Immunol. 2019;49(11):2051-2062. PubMed PMID: 31269241.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Statins can suppress DC-mediated Th2 responses through the repression of OX40-ligand and CCL17 expression. AU - Inagaki-Katashiba,Noriko, AU - Ito,Tomoki, AU - Inaba,Muneo, AU - Azuma,Yoshiko, AU - Tanaka,Akihiro, AU - Phan,Vien, AU - Kibata,Kayoko, AU - Satake,Atsushi, AU - Nomura,Shosaku, Y1 - 2019/07/11/ PY - 2018/11/02/received PY - 2019/05/16/revised PY - 2019/06/28/accepted PY - 2019/7/4/pubmed PY - 2020/5/27/medline PY - 2019/7/4/entrez KW - CCL17 KW - OX40L KW - myeloid DCs KW - statin KW - thymic stromal lymphopoietin (TSLP) SP - 2051 EP - 2062 JF - European journal of immunology JO - Eur J Immunol VL - 49 IS - 11 N2 - DCs and epithelial cell-derived thymic stromal lymphopoietin (TSLP) have pivotal roles in allergic inflammation. TSLP stimulates myeloid DCs to express OX40-ligand (OX40L) and CCL17, which trigger and maintain Th2 cell responses. We have previously shown that statins, which are HMG-CoA reductase inhibitors, have the ability to suppress type I IFN production by plasmacytoid DCs. Here, we extended our previous work to examine the immunomodulatory effect of statins on allergic responses, particularly the TSLP-dependent Th2 pathway induced by myeloid DCs. We found that treatment of TSLP-stimulated DCs with either pitavastatin or simvastatin suppressed both the DC-mediated inflammatory Th2 cell differentiation and CRTH2+ CD4+ memory Th2 cell expansion and also repressed the expressions of OX40L and CCL17 by DCs. These inhibitory effects of statins were mimicked by treatment with either a geranylgeranyl-transferase inhibitor or Rho-kinase inhibitor and were counteracted by the addition of mevalonate, suggesting that statins induce geranylgeranylated Rho inactivation through a mevalonate-dependent pathway. We also found that statins inhibited the expressions of phosphorylated STA6 and NF-κB-p50 in TSLP-stimulated DCs. This study identified a specific ability of statins to control DC-mediated Th2 responses, suggesting their therapeutic potential for treating allergic diseases. SN - 1521-4141 UR - https://www.unboundmedicine.com/medline/citation/31269241/Statins_can_suppress_DC_mediated_Th2_responses_through_the_repression_of_OX40_ligand_and_CCL17_expression_ L2 - https://doi.org/10.1002/eji.201847992 DB - PRIME DP - Unbound Medicine ER -