Mycophenolate mofetil reduces STAT3 phosphorylation in systemic lupus erythematosus patients

Slight-Webb, Samantha; Guthridge, Joel M.; Chakravarty, Eliza F.; Chen, Hua; Lu, Rufei; Macwana, Susan; Bean, Krista; Maecker, Holden T.; Utz, Paul J.; James, Judith A.

doi:10.1172/jci.insight.124575

Cited by 40 publications

(33 citation statements)

References 52 publications

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“…STAT3, an essential transcription factor in the pathogenesis of SLE [47], orchestrates multiple aspects of T cell function including regulating T cell activation, proliferation and Th17 cell differentiation [4,35]. In our previous study, we have demonstrated that STAT3 signaling positively regulated DN T cell proliferation in MRL/lpr mice [48].…”

Section: Discussionmentioning

confidence: 98%

Norcantharin ameliorates the development of murine lupus via limiting STAT3-mediated IL-17-producing cell accumulation

Du¹,

Feng²,

He³

et al. 2020

Preprint

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Background: Systemic lupus erythematosus (SLE), a devastating autoimmune disorder, results from the aberrant T cell and B cell activation. Norcantharin(NCTD), a derivative of Cantharidin, is an efficacious anti-cancer drug, whereas the role of NCTD in SLE remains unknown. As a result, we aimed to investigate the therapeutic effect of NCTD on the development of murine lupus.Methods: MRL/MpJ and MRL/ lpr female mice were randomly divided into three groups and administered with vehicle control or NCTD at 1 mg/kg or 2 mg/kg. The mortality rate, auto-antibodies, kidney damage, immune complex deposition and lupus-related inflammation level were tested. Furthermore, the proportion of T/B cells or T cell subsets in splenocytes from each group was monitored using flow cytometry. Finally, double-negative (CD3+CD4-CD8-, DN) T cell proliferation and T helper 17 (Th17) cell differentiation in vitro as well as regulatory pathways were analyzed for NCTD treatment.Results: NCTD decreased mortality, the accumulation of anti-dsDNA, splenomegaly and inflammation level of lupus mice. In addition, NCTD-treated MRL/ lpr mice showed notably ameliorated renal involvement. Moreover, we found that NCTD reduced DN T cell proliferation and Th17 differentiation via mediating the activation of signal transducer and activator of transcription 3 (STAT3). Conclusions: NCTD effectively suppressed DN T cell proliferation and Th17 cell polarization, thus ultimately contributing to the attenuated the SLE development. Our results revealed that NCTD may be a promising therapeutic agent for SLE.

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Section: Discussionmentioning

confidence: 98%

Norcantharin ameliorates the development of murine lupus via limiting STAT3-mediated IL-17-producing cell accumulation

Du¹,

Feng²,

He³

et al. 2020

Preprint

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“…O'Gorman and coworkers focused on specific chemokine signature in Systemic lupus erythematosus (SLE) patients and identified Toll‐like receptor activation 112 . Similarly, Slight‐Webb's groups applied CyTOF to reveal the STAT3 phosphorylation reduction after mycophenolate mofetil treatment in SLE 113 . Another study, with the aid of CyTOF, interrogated the circulatory reservoir of CD4 + subsets in juvenile idiopathic arthritis patients undergoing TNF‐alpha therapy withdrawal and found putative subsets prior to withdrawal that discriminated relapse from remission 111 .…”

Section: Applicationsmentioning

confidence: 99%

Progress and applications of mass cytometry in sketching immune landscapes

Zhang

Warden

2020

Clinical & Translational Med

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Recently emerged mass cytometry (cytometry by time-of-flight [CyTOF]) technology permits the identification and quantification of inherently diverse cellular systems, and the simultaneous measurement of functional attributes at the single-cell resolution. By virtue of its multiplex ability with limited need for compensation, CyTOF has led a critical role in immunological research fields. Here, we present an overview of CyTOF, including the introduction of CyTOF principle and advantages that make it a standalone tool in deciphering immune mysteries. We then discuss the functional assays, introduce the bioinformatics to interpret the data yield via CyTOF, and depict the emerging clinical and research applications of CyTOF technology in sketching immune landscape in a wide variety of diseases.

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“…It can often lead to renal injury and multiple organ damage due to the formation of autoantibodies against nuclear antigens, cell surface, and serum proteins [105]. Both STAT3 and STAT5 are implicated in SLE etiopathology and have been found activated in immune cells of SLE patients [106,107]. In T cells of SLE patients, STAT3 and STAT5 synergistically transactivate IL-10 through epigenetic remodeling [108].…”

Section: Stat3 and Stat5 Pathways In Inflammation And Melanoma-assmentioning

confidence: 99%

“…In this context, SLE has been recently associated with an active IL-17/STAT3 axis, accompanied by higher Th17 cell numbers [111]. STAT3 inhibitors in combination with immunosuppressive drugs, improve SLE via restoration of this balance [105], while agents inhibiting STAT3 phosphorylation have shown efficacy in the treatment of SLE [106]. STAT5 is also implicated in SLE, since activated STAT5 upregulates the antiapoptotic targets Bcl-2 and Ki-67 in CD4+ T cells, perhaps providing them with a survival and proliferative advantage over Treg cells [112].…”

Section: Stat3 and Stat5 Pathways In Inflammation And Melanoma-assmentioning

confidence: 99%

“…STAT3 inhibitors have demonstrated their efficacy in animal tumor models [121] and are currently under ongoing clinical trials for melanoma treatment (ClinicalTrials.gov Identifiers: NCT01904123, NCT03195699). In a similar manner, these inhibitory molecules are also efficient in treating several autoimmune diseases in vivo [85,106] and are now tested in a clinical anti-T1D setting (ClinicalTrials.gov Identifier: NCT02641522), which has been reported as melanoma-associated comorbidity. Moreover, it has been reported that cancer patients who exhibit cachexia may benefit from STAT3 inactivation, as it preserves fat and tissue mass and rescues cachectic phenotypes, in addition to eliminating tumors [122].…”

Section: Perspectives Challenges and Limitations Towards Translamentioning

confidence: 99%

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STAT3 and STAT5 Targeting for Simultaneous Management of Melanoma and Autoimmune Diseases

Logotheti

Pützer

2019

Cancers

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Melanoma is a skin cancer which can become metastatic, drug-refractory, and lethal if managed late or inappropriately. An increasing number of melanoma patients exhibits autoimmune diseases, either as pre-existing conditions or as sequelae of immune-based anti-melanoma therapies, which complicate patient management and raise the need for more personalized treatments. STAT3 and/or STAT5 cascades are commonly activated during melanoma progression and mediate the metastatic effects of key oncogenic factors. Deactivation of these cascades enhances antitumor-immune responses, is efficient against metastatic melanoma in the preclinical setting and emerges as a promising targeting strategy, especially for patients resistant to immunotherapies. In the light of the recent realization that cancer and autoimmune diseases share common mechanisms of immune dysregulation, we suggest that the systemic delivery of STAT3 or STAT5 inhibitors could simultaneously target both, melanoma and associated autoimmune diseases, thereby decreasing the overall disease burden and improving quality of life of this patient subpopulation. Herein, we review the recent advances of STAT3 and STAT5 targeting in melanoma, explore which autoimmune diseases are causatively linked to STAT3 and/or STAT5 signaling, and propose that these patients may particularly benefit from treatment with STAT3/STAT5 inhibitors.

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Mycophenolate mofetil reduces STAT3 phosphorylation in systemic lupus erythematosus patients

Cited by 40 publications

References 52 publications

Norcantharin ameliorates the development of murine lupus via limiting STAT3-mediated IL-17-producing cell accumulation

Norcantharin ameliorates the development of murine lupus via limiting STAT3-mediated IL-17-producing cell accumulation

Progress and applications of mass cytometry in sketching immune landscapes

STAT3 and STAT5 Targeting for Simultaneous Management of Melanoma and Autoimmune Diseases

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