Critical role for Stat3 in T-dependent terminal differentiation of IgG B cells

Fornek, Jamie L.; Tygrett, Lorraine T.; Waldschmidt, Thomas J.; Poli, Valeria; Rickert, Robert C.; Kansas, Geoffrey S.

doi:10.1182/blood-2005-07-2871

Cited by 132 publications

(131 citation statements)

References 32 publications

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“…STAT3 activation was recently shown to play an important role in the differentiation of B and Th17 cells [28] , particularly IL-21-mediated plasma cell differentiation, which is dependent upon pSTAT3 [29] . These findings, together with our data showing pSTAT3 suppression by UA, suggest that the reduced expression of B cell differentiation markers resulted from the inhibition of STAT3 phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

Ursolic acid ameliorates autoimmune arthritis via suppression of Th17 and B cell differentiation

Baek

Lee

et al. 2014

Acta Pharmacol Sin

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Aim: Ursolic acid (UA) is a pentacyclic triterpenoid found in most plant species, which has been shown anti-inflammatory and antioxidative activities. In this study, we examined the effects of UA on collagen-induced arthritis (CIA) in mice, and to identify the mechanisms underlying the effects. Methods: CIA was induced in mice. Two weeks later, the mice were treated with UA (150 mg/kg, ip, 3 times per week) for 4 weeks. The expression of cytokines and oxidative stress markers in joint tissues was measured with immunohistochemistry. The numbers of CD4 + IL-17 + , CD4 + CD25 + Foxp3 + and pSTAT3 cells in spleens were determined using confocal immunostaining or flowcytometric analyses. Serum antibody levels and B cell-associated marker mRNAs were analyzed with ELISAs and qRT-PCR, respectively. CD4 + T cells and CD19 + B cells were purified from mice spleens for in vitro studies. Results: UA treatment significantly reduced the incidence and severity of CIA-induced arthritis, accompanied by decreased expression of proinflammatory cytokines (TNF-α, IL-1β, IL-6, IL-21 and IL-17) and oxidative stress markers (nitrotyrosine and iNOS) in arthritic joints. In CIA mice, UA treatment significantly decreased the number of Th17 cells, while increased the number of Treg cells in the spleens, which was consistent with decreased expression of pSTAT3, along with IL-17 and RORγt in the splenocytes. In addition, UA treatment significantly reduced the serum CII-specific IgG levels in CIA mice. The inhibitory effects of UA on Th17 cells were confirmed in an in vitro model of Th17 differentiation. Furthermore, UA dose-dependently suppressed the expression of B cell-associated markers Bcl-6, Blimp1 and AID mRNAs in purified CD19 + B cells pretreated with IL-21 or LPS in vitro. Conclusion: UA treatment significantly ameliorates CIA in mice via suppression of Th17 and differentiation. By targeting pathogenic Th17 cells and autoantibody production, UA may be useful for the treatment of autoimmune arthritis and other Th17-related diseases.

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Section: Discussionmentioning

confidence: 99%

Ursolic acid ameliorates autoimmune arthritis via suppression of Th17 and B cell differentiation

Baek

Lee

et al. 2014

Acta Pharmacol Sin

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“…Moreover, IL-6 is a immunomodulatory cytokine that was systemically high in the serum. It controls plasma B-cell differentiation, and it influences also T helper cell cytokine production through Stat3-dependent signaling (1,(25)(26)(27). Stat3 isoforms are known to cooperate with c-Jun or JunD proteins specifically (33).…”

Section: Discussionmentioning

confidence: 99%

“…S4 I and E), indicating that G-CSF is not responsible for the autoimmune phenotype. IL-6-Jak1-Stat3 activation promotes plasma B-cell differentiation either directly (26) or indirectly through CD4 ϩ T helper cells (27). To investigate the role of lymphocytes in the development of local and systemic autoimmune alterations, JunB ⌬ep mice were crossed with Rag2 Ϫ/Ϫ mice.…”

Section: Sle Phenotype By Junb ⌬Ep and Rescue By Il-6mentioning

confidence: 99%

Epidermal loss of JunB leads to a SLE phenotype due to hyper IL-6 signaling

Pflegerl

Vesely

Hantusch

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Zhu et al 15 found that IL-21 upregulated NKG2D expression on NK cells via phosphorylation of STAT3. In addition, STAT3 signaling is required for regulation of terminal differentiation of IgG B cells, 16 maintenance of Th17 cells, 17 and development of memory T cells. 18 However, whether STAT3 plays a role in regulation of NKG2D expression on CD8 C T cells has yet to be determined.…”

Section: Introductionmentioning

confidence: 99%

Regulation of NKG2D⁺CD8⁺T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

Batth

Xia

et al. 2016

OncoImmunology

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The natural killer (NK) group 2D (NKG2D) receptor, which displays on mouse and human NK cells, activates CD8 C T cells and small subsets of other T cells. NKG2D C CD8 C T cells play critical roles in both innate and adaptive immunity upon engagement with NKG2D ligands to eliminate tumor and infected cells. Despite the important role of NKG2D C CD8 C T cells in immune surveillance, the mechanisms of how NKG2D expression on CD8 C T cells is regulated remain poorly defined. We treated mouse and human CD8 C T cells with CD80 recombinant protein, plus a pharmacologic model with small molecular inhibitors to determine which signaling pathway leads to NKG2D regulation on CD8 C T cells. This study revealed that CD28 activation gives rise to sustained NKG2D expression on both mouse and human CD8 C T cells in a signal transducer and activator of transcription 3 (STAT3) phosphorylation-dependent manner. Further, we found that CD28 activation stimulated sustained activation of the tyrosine kinase Lck, which recruits and triggers Janus kinase/STAT3 signaling to phosphorylate STAT3, and in turn increases NKG2D expression. Moreover, NKG2D induction on CD8 C T cells exerts cytolytic activity against target tumor cells in vitro, as well as significantly improves the antitumor therapeutic effects in vivo in an NKG2D-dependent manner. Taken together, these results elucidated a novel mechanism of NKG2D regulation by phosphorylated STAT3 (pSTAT3) on CD8 C T cells upon CD28 activation. This mechanism may shed light on the effectiveness of CD80-based, NKG2D-dependent antitumor immunotherapy.

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Critical role for Stat3 in T-dependent terminal differentiation of IgG B cells

Cited by 132 publications

References 32 publications

Ursolic acid ameliorates autoimmune arthritis via suppression of Th17 and B cell differentiation

Ursolic acid ameliorates autoimmune arthritis via suppression of Th17 and B cell differentiation

Epidermal loss of JunB leads to a SLE phenotype due to hyper IL-6 signaling

Regulation of NKG2D⁺CD8⁺T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

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Critical role for Stat3 in T-dependent terminal differentiation of IgG B cells

Cited by 132 publications

References 32 publications

Ursolic acid ameliorates autoimmune arthritis via suppression of Th17 and B cell differentiation

Ursolic acid ameliorates autoimmune arthritis via suppression of Th17 and B cell differentiation

Epidermal loss of JunB leads to a SLE phenotype due to hyper IL-6 signaling

Regulation of NKG2D+CD8+T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism

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Regulation of NKG2D⁺CD8⁺T-cell-mediated antitumor immune surveillance: Identification of a novel CD28 activation-mediated, STAT3 phosphorylation-dependent mechanism