{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:33:17Z","timestamp":1792607597130,"version":"4.5.0"},"reference-count":31,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2019,4,26]]},"abstract":"<jats:sec>\n                    <jats:title>\n                      <jats:underline>Rationale:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>Targeting inflammation has been shown to provide clinical benefit in the field of cardiovascular diseases. Although manipulating regulatory T-cell function is an important goal of immunotherapy, the molecules that mediate their suppressive activity remain largely unknown. IL (interleukin)-35, an immunosuppressive cytokine mainly produced by regulatory T cells, is a novel member of the IL-12 family and is composed of an EBI3 (Epstein-Barr virus\u2013induced gene 3) subunit and a p35 subunit. However, the role of IL-35 in infarct healing remains elusive.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Objective:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>This study aimed to determine whether IL-35 signaling is involved in healing and cardiac remodeling after myocardial infarction (MI) and, if so, to elucidate the underlying molecular mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Methods and Results:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      IL-35 subunits (EBI3 and p35), which are mainly expressed in regulatory T cells, were upregulated in mice after MI. After IL-35 inhibition, mice showed impaired infarct healing and aggravated cardiac remodeling, as demonstrated by a significant increase in mortality because of cardiac rupture, decreased wall thickness, and worse cardiac function compared with wild-type MI mice. IL-35 inhibition also led to decreased expression of \u03b1-SMA (\u03b1-smooth muscle actin) and collagen I\/III in the hearts of mice after MI. Pharmacological inhibition of IL-35 suppressed the accumulation of Ly6C\n                      <jats:sup>low<\/jats:sup>\n                      and major histocompatibility complex II\n                      <jats:sup>low<\/jats:sup>\n                      \/C-C motif chemokine receptor type 2\n                      <jats:sup>\u2212<\/jats:sup>\n                      (MHC II\n                      <jats:sup>low<\/jats:sup>\n                      CCR2\n                      <jats:sup>\u2212<\/jats:sup>\n                      ) macrophages in infarcted hearts. IL-35 activated transcription of CX3CR1 (C-X3-C motif chemokine receptor 1) and TGF (transforming growth factor) \u03b21 in macrophages by inducing GP130 signaling, via IL12R\u03b22 and phosphorylation of STAT1 (signal transducer and activator of transcription family) and STAT4 and subsequently promoted Ly6C\n                      <jats:sup>low<\/jats:sup>\n                      macrophage survival and extracellular matrix deposition. Moreover, compared with control MI mice, IL-35\u2013treated MI mice showed increased expression of \u03b1-SMA and collagen within scars, correlating with decreased left ventricular rupture rates.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Conclusions:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      IL-35 reduces cardiac rupture, improves wound healing, and attenuates cardiac remodeling after MI by promoting reparative CX3CR1\n                      <jats:sup>+<\/jats:sup>\n                      Ly6C\n                      <jats:sup>low<\/jats:sup>\n                      macrophage survival.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.118.314569","type":"journal-article","created":{"date-parts":[[2019,3,5]],"date-time":"2019-03-05T05:00:23Z","timestamp":1551762023000},"page":"1323-1336","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":131,"title":["Interleukin-35 Promotes Macrophage Survival and Improves Wound Healing After Myocardial Infarction in Mice"],"prefix":"10.1161","volume":"124","author":[{"given":"Daile","family":"Jia","sequence":"first","affiliation":[{"name":"From the Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China (D.J., H.J., X.W., J.W., W.Y., Z.W., K.H., A.S., J.G.)"},{"name":"Shanghai Institute of Cardiovascular Diseases, Shanghai, China (D.J., H.J., X.W., J.W., W.Y., Z.W., K.H., A.S., J.G.)"},{"name":"NHC Key Laboratory of Viral Heart Diseases, Shanghai, China (D.J., H.J., X.W., J.W., W.Y., Z.W., K.H., A.S., J.G.)"},{"name":"Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, China (D.J., H.J., X.W., J.W., W.Y., Z.W., K.H., A.S., J.G.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Jiang","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China (D.J., H.J., X.W., J.W., W.Y., Z.W., K.H., A.S., J.G.)"},{"name":"Shanghai Institute of Cardiovascular Diseases, Shanghai, China (D.J., H.J., X.W., J.W., W.Y., Z.W., K.H., A.S., J.G.)"},{"name":"NHC Key Laboratory of Viral Heart Diseases, Shanghai, China (D.J., H.J., X.W., J.W., W.Y., Z.W., K.H., A.S., J.G.)"},{"name":"Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, China (D.J., H.J., X.W., J.W., W.Y., Z.W., K.H., A.S., J.G.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Weng","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China (D.J., H.J., X.W., J.W., W.Y., Z.W., K.H., A.S., J.G.)"},{"name":"Shanghai Institute of Cardiovascular Diseases, Shanghai, China (D.J., H.J., X.W., J.W., W.Y., Z.W., K.H., A.S., J.G.)"},{"name":"NHC Key Laboratory of Viral Heart Diseases, Shanghai, China (D.J., H.J., X.W., J.W., W.Y., Z.W., K.H., A.S., J.G.)"},{"name":"Key Laboratory of Viral Heart Diseases, Chinese Academy of Medical Sciences, China (D.J., H.J., X.W., J.W., W.Y., Z.W., K.H., A.S., J.G.)"},{"name":"Institutes of Biomedical Sciences, Fudan University, Shanghai, China (X.W., J.W., Z.W., A.S., J.G.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wu","sequence":"additional","affiliation":[{"name":"From the Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China (D.J., H.J., X.W., J.W., W.Y., Z.W., K.H., A.S., J.G.)"},{"name":"Shanghai Institute of Cardiovascular Diseases, Shanghai, China (D.J., H.J., X.W., J.W., W.Y., Z.W., K.H., A.S., J.G.)"},{"name":"NHC Key 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