IL-4 blocks TH1-polarizing/inflammatory cytokine gene expression during monocyte-derived dendritic cell differentiation through histone hypoacetylation

López-Bravo, Marı́a; Escalera, María Minguito de la; Domínguez, Pilar M.; González-Cintado, Leticia; Fresno, Carlos del; Martı́n, Pilar; Hoyo, Gloria Martı́nez del; Ardavı́n, Carlos

doi:10.1016/j.jaci.2013.08.039

Cited by 20 publications

(13 citation statements)

References 28 publications

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“…Therefore, we examined this possibility in vitro. We not only confirmed that IL-4 independently induces macrophage polarization in vitro, but further demonstrated that the effects of IL-4 on macrophage polarization may involve histone deacetylation, consistent with previous studies on IL-4 in different models [29][30][31][32][33].…”

Section: Il-4 Induced M1-to-m2 Macrophage Polarization In Vitro Posssupporting

confidence: 91%

“…In vivo treatment with IL-4 was effective in various autoimmune models, including collagen-induced arthritis [21][22][23][24][25] and proteoglycan-induced arthritis (PGIA) [20], mouse models for AS. This is due to the fact that IL-4 acts as an anti-inflammatory cytokine that modulates macrophage polarization and activity through suppression of Th1-mediated pro-inflammatory effects and enhancement of Th2-mediate anti-inflammatory effects [26][27][28], possibly via modulation of histone deacetylation [29][30][31][32][33]. M2 macrophages are typically found in Th2-dominated responses, as the Th2-driving IL-4 is a strong inducer of M2 polarization [15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 99%

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IL-4 Modulates Macrophage Polarization in Ankylosing Spondylitis

Lin

Qiu

Chen

2015

Cell Physiol Biochem

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Background/Aims: Osteoclasts (OC) originate from monocytes/macrophages and play a critical role in the development of ankylosing spondylitis (AS). Receptor activator of NF-kB ligand (RANKL) is critical for the differentiation and maturation of OC from monocytes/macrophages, the underlying mechanisms of which processes have not been completely elucidated. Interleukin 4 (IL-4) attenuates the pathogenesis of AS via ill-defined mechanisms. Methods: We used a proteoglycan-induced arthritis (PGIA) model in Balb/c mice to study AS in humans. We injected IL-4 into the articular cavity and evaluated its effects on PGIA by incidence of arthritis, clinical and pathological arthritis severity and PET tracer uptake. We isolated and analyzed the number and polarization of macrophages in the articular cavity before and after IL-4 treatment. We analyzed RANKL levels in macrophage subtypes. We then isolated bone-marrow derived macrophages and treated them with IL-4 in vitro, with or without histone deacetylase inhibitors trichostatin A (TSA), and then analyzed the polarization of cultured macrophages before and after IL-4 treatment and RANKL levels in macrophage subtypes. Results: IL-4 treatment decreased the incidence and severity of arthritis in a mouse AS model, and polarized macrophages from a classical M1 subtype to an M2 subtype in vivo and in vitro. RANKL was predominantly produced by M1, but not by M2 macrophages. IL-4-mediated inhibition of RANKL in macrophages was abolished by TSA. Conclusion: Our data suggest that the therapeutic effects of IL-4 on AS may result from a M1-to-M2 macrophage polarization and its inhibition of RANKL expression on macrophages, possibly through enhanced histone deacetylation.

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Section: Il-4 Induced M1-to-m2 Macrophage Polarization In Vitro Posssupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

IL-4 Modulates Macrophage Polarization in Ankylosing Spondylitis

Lin

Qiu

Chen

2015

Cell Physiol Biochem

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“…In view of the similarities found between the effects of OP and RA, and the earlier finding that IL-4 and IL-13 work together with RA to instruct DCs to acquire a mucosal phenotype and function [5,28,29], we tested the influence of IL-4 on the effects of OP. Activation of BM-DCs with IL-4 alone increased the expression of Aldh1a2, Tgfb1, Csf2, and the Th2-skewing factors [30,31]: Il33, Jag2, Tnfsf4, and Irf4 ( Figure 1), but, in agreement with previous findings, IL-4 did not enhance Il6 or Il10 expression [32]. As expected, IL-4 synergised with RA to increase Aldh1a2 expression in BM-DCs [5,29], and it considerably enhanced Il33 expression.…”

Section: Il-4 Enhances the Effects Of The Hydrolysate Of Ovalbumin Wisupporting

confidence: 90%

“…Our results, showing abrogation of Foxp3 induction by OP+IL-4 when RALDH activity was inhibited with DEAB, indicate that direct RA production by CD4 + T cells themselves favoured Treg generation. Of note, the availability of IL-6 in a Th2-dominated environment, that could arise from the combined action of TLR activation and IL-4 [32], would favour the generation of Treg cells bearing simultaneously the transcription factors Foxp3 and RORγt, since TGF-β plus IL-6 open the RORγt differentiation pathway and additional RA favours the generation of double-positive cells in vitro [14].…”

Section: Discussionmentioning

confidence: 99%

Ovalbumin-Derived Peptides Activate Retinoic Acid Signalling Pathways and Induce Regulatory Responses Through Toll-Like Receptor Interactions

et al. 2020

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This study investigates the potential of a hydrolysate of ovalbumin with pepsin (OP) to preclude Th2-type immunity by the enhancement of tolerogenic dendritic cells (DCs) and regulatory T (Treg) cells. Through Toll-like receptor (TLR) stimulation, OP enhances the retinoic acid pathway on DCs by means of the induction of aldehyde dehydrogenase enzymes and transforming growth factor beta (TGF-β), and it confers upon DC the ability to upregulate interleukin 10 (IL-10) as well as other tolerance-promoting mediators downstream of TRL signalling, such as IL-27, IL-33, Notch ligands, OX40L, and the transcription factors IRF4 and IRF8. OP-conditioned DCs induce the expansion of Foxp3+ and Tr1 cells in co-culture with CD4+ T cells. Furthermore, OP directly conditions CD4+ T cells from naïve mice, without the mediation of DCs, to express aldehyde dehydrogenase (ALDH) enzymes and, in the presence of the Th2 cytokine IL-4 and exogenous TGF-β, it enhances Foxp3 expression. It is noteworthy that, on CD4+ T cells isolated from egg-allergic mice, OP significantly enriches the levels of Foxp3+ and Foxp3+ RORγt+ CD4+ T cells. In conclusion, we show that food peptides may work, analogously to microbial-driven signals, through TLRs, to promote a tolerogenic phenotype on cells of the innate and adaptive immune system, a property that is further enhanced in the context of a Th2 cytokine-rich environment.

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“…Although the first mechanism of monocyteinduced T cell suppression described above has been demonstrated multiple times, the other two mechanisms require further confirmation and investigation. In conclusion, various studies suggest that the functional role of LY6C + monocytes is largely dictated by the pathogen or inflammatory environment they encounter 79,[124][125][126] .…”

Section: Box 2 | Classical Dendritic Cell Subsets In Cross-presentationmentioning

confidence: 92%

Monocyte differentiation and antigen-presenting functions

Jakubzick¹,

Randolph

Henson³

2017

Nat Rev Immunol

658

641

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Monocytes develop in the bone marrow and represent the primary type of mononuclear phagocyte found in the blood. They were long thought of as a source for tissue macrophages, but recent studies indicate more complex roles for monocytes, both within the circulation and after their migration into tissues and lymphoid organs. In this Review, we discuss the newer concepts underlying the maturation of emigrating monocytes into different classes of tissue macrophages, as well as their potential functions, as monocyte-derived cells, in the tissues. In addition, we consider the emerging roles for monocytes in adaptive immunity as antigen-presenting cells.

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IL-4 blocks TH1-polarizing/inflammatory cytokine gene expression during monocyte-derived dendritic cell differentiation through histone hypoacetylation

Cited by 20 publications

References 28 publications

IL-4 Modulates Macrophage Polarization in Ankylosing Spondylitis

IL-4 Modulates Macrophage Polarization in Ankylosing Spondylitis

Ovalbumin-Derived Peptides Activate Retinoic Acid Signalling Pathways and Induce Regulatory Responses Through Toll-Like Receptor Interactions

Monocyte differentiation and antigen-presenting functions

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