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

Imbrechts, Maya; Samblancx, Karen De; Fierens, Karlien; Brisse, Ellen; Vandenhaute, Jessica; Mitera, Tania; Libert, Claude; Smets, Ide; Wouters, Carine; Matthys, Patrick

doi:10.1002/eji.201847578

Cited by 16 publications

(10 citation statements)

References 98 publications

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“…However, our ex vivo and in vitro data did not underpin a negative or positive direct effect of BAFF or BAFF-R shift on IL-10 production. As a positive control, we replicated the previously described effects of IFN-β and CpG on B cell IL-10 production ( 31 , 32 ), but this is independent of and not augmented by a BAFF stimulus under treatment. This contrasts with animal data and human data from lymphoproliferative or other autoimmune diseases showing the involvement of BAFF in inducing a regulatory B cell phenotype through TACI signalling ( 33 , 34 ).…”

Section: Discussionsupporting

confidence: 83%

“…They are enriched for IL-10 producing cells, and any shift towards transitional B cells would increase these cells proportionally. However, all B cell subsets, including naïve and memory subsets, are able to produce IL-10 ( 7 , 32 ). In addition, a reduction in memory B cells decreases the pro-inflammatory state of the immune system ( 8 ).…”

Section: Discussionmentioning

confidence: 99%

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Treatment-Induced BAFF Expression and B Cell Biology in Multiple Sclerosis

et al. 2021

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Although fingolimod and interferon-β are two mechanistically different multiple sclerosis (MS) treatments, they both induce B cell activating factor (BAFF) and shift the B cell pool towards a regulatory phenotype. However, whether there is a shared mechanism between both treatments in how they influence the B cell compartment remains elusive. In this study, we collected a cross-sectional study population of 112 MS patients (41 untreated, 42 interferon-β, 29 fingolimod) and determined B cell subsets, cell-surface and RNA expression of BAFF-receptor (BAFF-R) and transmembrane activator and cyclophilin ligand interactor (TACI) as well as plasma and/or RNA levels of BAFF, BAFF splice forms and interleukin-10 (IL-10) and -35 (IL-35). We added an in vitro B cell culture with four stimulus conditions (Medium, CpG, BAFF and CpG+BAFF) for untreated and interferon-β treated patients including measurement of intracellular IL-10 levels. Our flow experiments showed that interferon-β and fingolimod induced BAFF protein and mRNA expression (P ≤ 3.15 x 10-4) without disproportional change in the antagonizing splice form. Protein BAFF correlated with an increase in transitional B cells (P = 5.70 x 10-6), decrease in switched B cells (P = 3.29 x 10-4), and reduction in B cell-surface BAFF-R expression (P = 2.70 x 10-10), both on TACI-positive and -negative cells. TACI and BAFF-R RNA levels remained unaltered. RNA, plasma and in vitro experiments demonstrated that BAFF was not associated with increased IL-10 and IL-35 levels. In conclusion, treatment-induced BAFF correlates with a shift towards transitional B cells which are enriched for cells with an immunoregulatory function. However, BAFF does not directly influence the expression of the immunoregulatory cytokines IL-10 and IL-35. Furthermore, the post-translational mechanism of BAFF-induced BAFF-R cell surface loss was TACI-independent. These observations put the failure of pharmaceutical anti-BAFF strategies in perspective and provide insights for targeted B cell therapies.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Treatment-Induced BAFF Expression and B Cell Biology in Multiple Sclerosis

et al. 2021

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“…Furthermore, we recently reported that IFN-g significantly increases IL-10 production when mouse and human B cells (from naive mice and healthy donors, respectively) are triggered with the TLR9 ligand CpG. This stimulatory effect of IFN-g on CpG-induced IL-10 was restricted to B cells and found to be dependent on the MAPKs p38 and JNK (48). Because CFA is an oil adjuvant with heat-killed mycobacteria containing the TLR9 ligand CpG (49), it is intriguing to speculate that the defective IL-10 production by B cells in CFA-injected IFN-g KO mice, as opposed to WT mice, may be conditioned by CpG.…”

Section: Discussionmentioning

confidence: 95%

Insufficient IL-10 Production as a Mechanism Underlying the Pathogenesis of Systemic Juvenile Idiopathic Arthritis

Imbrechts

Avau

Vandenhaute

et al. 2018

The Journal of Immunology

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Systemic juvenile idiopathic arthritis (sJIA) is a childhood-onset immune disorder of unknown cause. One of the concepts is that the disease results from an inappropriate control of immune responses to an initially harmless trigger. In the current study, we investigated whether sJIA may be caused by defects in IL-10, a key cytokine in controlling inflammation. We used a translational approach, with an sJIA-like mouse model and sJIA patient samples. The sJIA mouse model relies on injection of CFA in IFN-g-deficient BALB/c mice; corresponding wild type (WT) mice only develop a subtle and transient inflammatory reaction. Diseased IFN-g-deficient mice showed a defective IL-10 production in CD4 + regulatory T cells, CD19 + B cells, and CD3 2 CD122 + CD49b + NK cells, with B cells as the major source of IL-10. In addition, neutralization of IL-10 in WT mice resulted in a chronic immune inflammatory disorder clinically and hematologically reminiscent of sJIA. In sJIA patients, IL-10 plasma levels were strikingly low as compared with proinflammatory mediators. Furthermore, CD19 + B cells from sJIA patients showed a decreased IL-10 production, both ex vivo and after in vitro stimulation. In conclusion, IL-10 neutralization in CFA-challenged WT mice converts a transient inflammatory reaction into a chronic disease and represents an alternative model for sJIA in IFN-g-competent mice. Cell-specific IL-10 defects were observed in sJIA mice and patients, together with an insufficient IL-10 production to counterbalance their proinflammatory cytokines. Our data indicate that a defective IL-10 production contributes to the pathogenesis of sJIA.

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“…Although this cytokine is known to be able to inhibit IL‐10 production in monocytes, it can also have regulatory functions. In combination with CpG stimulation, IFN‐γ could spike IL‐10 production in B cells, and these B cells were capable of inhibiting T cell proliferation 100 …”

Section: How To Induce Breg Cellsmentioning

confidence: 99%

B regulatory cells in allergy

Satitsuksanoa

Jansen

et al. 2020

Immunological Reviews

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B cells have classically been recognized for their unique and indispensable role in the production of antibodies. Their potential as immunoregulatory cells with anti‐inflammatory functions has received increasing attention during the last two decades. Herein, we highlight pioneering studies in the field of regulatory B cell (Breg) research. We will review the literature on Bregs with a particular focus on their role in the regulation of allergic inflammation.

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

Cited by 16 publications

References 98 publications

Treatment-Induced BAFF Expression and B Cell Biology in Multiple Sclerosis

Treatment-Induced BAFF Expression and B Cell Biology in Multiple Sclerosis

Insufficient IL-10 Production as a Mechanism Underlying the Pathogenesis of Systemic Juvenile Idiopathic Arthritis

B regulatory cells in allergy

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