IL-10 production by B cells is differentially regulated by immune-mediated and infectious stimuli and requires p38 activation

Mion, Francesca; Tonon, Silvia; Toffoletto, Barbara; Cesselli, Daniela; Pucillo, Carlo; Vitale, Gaetano

doi:10.1016/j.molimm.2014.05.018

Cited by 36 publications

(26 citation statements)

References 35 publications

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“…In B cells, these pathways are less well described. In line with some previous reports, we showed that the MAPKs ERK1/2, p38 and JNK are implicated in CpG‐induced IL‐10 production in human B cells . It has been described that IFN‐γ negatively regulates TLR‐induced IL‐10 through the ERK1/2, p38 and PI3K signalling pathways in macrophages .…”

Section: Discussionsupporting

confidence: 92%

“…In monocytes and macrophages, the MAPKs c‐Jun N‐terminal kinases (JNK), p38 and ERK1/2 are involved in TLR‐induced IL‐10 production and are tightly controlled by IFN‐γ . In B cells, it has been demonstrated that p38, JNK and ERK1/2 are important for IL‐10 production . We confirmed the importance of these MAPKs in IL‐10 production by B cells.…”

Section: Resultssupporting

confidence: 74%

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IFN‐γ stimulates CpG‐induced IL‐10 production in B cells via p38 and JNK signalling pathways

et al. 2018

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The production of IL-10, a potent immunosuppressive cytokine, must be strictly regulated to ensure a balanced immune response. IFN-γ, a key cytokine in multiple immune processes and pathologies, is known as an inhibitor of IL-10 production by monocytes and macrophages, but also has some regulatory functions. In the present study, we explored the role of IFN-γ on Toll-like receptor (TLR)-induced IL-10 production in murine peritoneal and spleen cells and in human peripheral blood mononuclear cells. IFN-γ inhibited IL-10 production induced by TLR2, TLR3, TLR4 and TLR7/8 agonists, but stimulated IL-10 production when cells were triggered with CpG oligodeoxynucleotides, a specific TLR9 agonist. The stimulatory effect of IFN-γ on TLR9-induced IL-10 was restricted to B cells. In line with the increased IL-10, B cells stimulated with CpG and IFN-γ profoundly inhibited CD4 T cell proliferation. Further research into the mechanisms involved, revealed that the mitogen-activated protein kinases p38 and JNK are essential players in this stimulatory effect, and that the phosphatase MKP1 - an inhibitor of p38 and JNK activity - is downregulated after combined stimulation with IFN-γ and CpG. Our data may represent a novel immunoregulatory role of IFN-γ in B cells after triggering of TLR9, by stimulating IL-10 production.

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Section: Discussionsupporting

confidence: 92%

Section: Resultssupporting

confidence: 74%

IFN‐γ stimulates CpG‐induced IL‐10 production in B cells via p38 and JNK signalling pathways

et al. 2018

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“…In patients with SSc, Breg cell deficiency was characterized by impaired activation of p38 MAPK and STAT‐3 in naive and memory B cells, irrespective of the stimulus. This reinforces the findings of previous studies showing that IL‐10 production by B cells is dependent on the activation of p38 MAPK and STAT‐3 .…”

Section: Discussionsupporting

confidence: 91%

“…In view of the reported data suggesting that IL‐10 production by B cells stimulated through the TLRs is dependent on the activation of p38 MAPK and STAT‐3 , we investigated the effects of stimulation with ODN2006 (CpG ligand for TLR‐9) on the phosphorylation of these signaling molecules in naive and memory B cells from SSc patients. We also examined the effects of BCR‐specific stimulation using polyclonal IgM.…”

Section: Resultsmentioning

confidence: 99%

Breg Cells Are Numerically Decreased and Functionally Impaired in Patients With Systemic Sclerosis

Mavropoulos

Simopoulou

Varna

et al. 2016

Arthritis & Rheumatology

128

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Objective Breg cells, a regulatory cell subset that produces interleukin‐10 (IL‐10), play a significant role in suppressing autoimmune responses and preventing autoimmunity. This study was undertaken to examine the number and function of Breg cells in patients with systemic sclerosis (SSc), a disease with many autoantibodies. Methods Forty‐five patients with SSc (12 with early SSc, 33 with established disease including 16 with SSc‐associated pulmonary fibrosis [PF]), 12 healthy control subjects, and 10 patients with rheumatoid arthritis (RA)–associated PF were studied. The phenotypes of immature/transitional Breg cells (CD19+CD24highCD38high) and memory Breg cells (CD19+CD27+CD24high) were evaluated by flow cytometry. The function of Breg cells was assessed by measuring the production of IL‐10 after B cell activation. In addition, activation of p38 MAPK and STAT‐3 was measured following stimulation of the cells with B cell receptor (BCR) and Toll‐like receptor 9 (TLR‐9). Results Percentages of memory Breg cells were decreased in patients with early SSc (mean ± SEM 1.85 ± 0.38%), those with established SSc (1.6 ± 0.88%), those with SSc‐associated PF (1.52 ± 0.17%), and those with RA‐associated PF (1.58 ± 0.26%), compared to healthy controls (6.3 ± 0.49%; each P < 0.001). Percentages of transitional Breg cells were also decreased. Expression of IL‐10 by Breg cells after stimulation with TLR‐9 was impaired in patients with SSc, particularly those with SSc‐associated PF. Activation of STAT‐3 and p38 MAPK was impaired in naive and memory B cells from patients with SSc after stimulation with BCR and TLR‐9. Expression of the stimulatory CD19 receptor was increased in B cells and also increased, to a lesser extent, in Breg cells from patients with SSc compared to healthy controls. Percentages of memory B cells were decreased in patients with SSc, particularly in those with SSc‐associated PF. Conclusion This is the first study to demonstrate that Breg cells are phenotypically and functionally impaired in patients with SSc. Furthermore, in SSc, B cells exhibit impaired p38 MAPK and STAT‐3 activation upon stimulation with BCR and TLR‐9. The findings of decreased numbers of Breg cells along with increased expression of CD19 support the idea of B cell autoaggression acting as an immunopathogenic mediator in SSc.

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“…Initial studies have revealed the participation of diverse pathways in IL-10 production by B cells such as IRF4 [40,85], p38 [86], STAT3, and ERK [87]. Foxp3 is a transcription factor involved in the development and function of regulatory T cells and in the negative regulation of immune responses [88].…”

Section: Discussionmentioning

confidence: 99%

Regulatory B Cells and Mechanisms

Rincón‐Arévalo

Sanchez-Parra

Castaño

et al. 2015

International Reviews of Immunology

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Regulatory B cells have gained prominence in their role as modulators of the immune response against tumors, infectious diseases, and autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis, among others. The concept of regulatory B cells has been strongly associated with interleukin (IL)-10 production; however, there is growing evidence that supports the existence of other regulatory mechanisms, such as the production of transforming growth factor β (TGF-β), induced cell death of effector T cells, and the induction of CD4(+)CD25(-)Foxp3(+) regulatory T cells. The regulatory function of B cells has been associated with the presence and activation of molecules such as CD40, CD19, CD1d, and BCR. Alterations in signaling by any of these pathways leads to a marked defect in regulatory B cells and to increased clinical symptoms and proinflammatory signs, both in murine models and in autoimmune diseases in humans. B cells mainly exert their regulatory effect through the inhibition of proliferation and production of proinflammatory mediators, such as TNF-α, IFN-γ, and IL-17 by CD4(+) T cells. A better understanding of how regulatory B cells function will offer new perspectives with regard to the treatment of various human diseases.

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IL-10 production by B cells is differentially regulated by immune-mediated and infectious stimuli and requires p38 activation

Cited by 36 publications

References 35 publications

IFN‐γ stimulates CpG‐induced IL‐10 production in B cells via p38 and JNK signalling pathways

IFN‐γ stimulates CpG‐induced IL‐10 production in B cells via p38 and JNK signalling pathways

Breg Cells Are Numerically Decreased and Functionally Impaired in Patients With Systemic Sclerosis

Regulatory B Cells and Mechanisms

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