Identification and characterization of a human IL-10 receptor antagonist

Naiyer, Mohammed M.; Saha, Shipra; Hemke, Vijayshree; Roy, Somenath; Singh, Shailza; Krishnasastry, M.V.; Saha, Bhaskar

doi:10.1016/j.humimm.2012.09.002

Cited by 15 publications

(11 citation statements)

References 15 publications

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“…Mesenchymal stem cells from rat bone marrow down-modulated the maturation of murine dendritic cells when IL10 triggered the JAK1/STAT3 signaling pathway [44]. Furthermore, IL10 and STAT3 are involved in the increased susceptibility to infections caused by Leishmania amazonensis, Leishmania donovani, the Newcastle disease virus, and Listeria monocytogenes [45][46][47][48]. According to our present data, IL10 also promoted higher infectivity during T. gondii infection in murine dendritic cells [49], and increased IL10 levels were associated with the high susceptibility to reinfection with different recombinant T. gondii strains in BALB/c mice [50].…”

Section: Discussionmentioning

confidence: 99%

IL10, TGF Beta1, and IFN Gamma Modulate Intracellular Signaling Pathways and Cytokine Production to Control Toxoplasma gondii Infection in BeWo Trophoblast Cells1

Barbosa

Lopes-Maria

Gomes

et al. 2015

Biology of Reproduction

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Considering that interleukin 10 (IL10), transforming growth factor beta1 (TGFB1), and interferon gamma (IFNG) are involved in the susceptibility of BeWo trophoblast cells to Toxoplasma gondii infection, the aim of the present study was to investigate the effector mechanisms triggered by these cytokines in the control of T. gondii in BeWo cells. For this purpose, infected/uninfected BeWo cells were treated with IL10, TGFB1 (50 ng/ml), and IFNG (20 or 100 ng/ml) in order to verify the phosphorylation of signal transducers and activators of transcription 1 (STAT1), STAT3, and Smad2, parasite intracellular proliferation, as well as the Th1/Th2/IL17A cytokine production. The treatment of BeWo cells with IL10 and TGFB1 favored T. gondii proliferation, and these findings were associated with STAT3 and Smad2 phosphorylation, respectively (P < 0.05). Also, these cytokine treatments were able to down-modulate TNF alpha (TNFA) and IL6 production (P < 0.05). Low concentration of IFNG was unable to control T. gondii infection but was able to trigger STAT1 phosphorylation and up-regulate IL6 and IL17A production; whereas a high concentration of IFNG was unable to activate STAT1 but down-modulated IL6 and TNFA and increased T. gondii proliferation (P < 0.05). IL10, TGFB1, and IFNG regulate a differential T. gondii proliferation in BeWo cells because they distinctly trigger intracellular signaling pathways and cytokine production, especially IL6 and TNFA. Our data open new windows to understand the mechanisms triggered by IL10, TGFB1, and IFNG at the maternal-fetal interface in the presence of T. gondii, contributing to recognizing the importance of these effector mechanisms involved in the vertical transmission of this parasite.

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Section: Discussionmentioning

confidence: 99%

IL10, TGF Beta1, and IFN Gamma Modulate Intracellular Signaling Pathways and Cytokine Production to Control Toxoplasma gondii Infection in BeWo Trophoblast Cells1

Barbosa

Lopes-Maria

Gomes

et al. 2015

Biology of Reproduction

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“…A similar effect on has been reported by blocking IL-1R signaling and by using IL-1ra in mice (Wu et al, 2011). It would be interesting to evaluate the behavioral response to EtOH using an IL-10R antagonist, but such a compound is not yet available commercially, albeit a human IL-10R peptide antagonist has been recently described (Naiyer et al, 2013). Given that anti-inflammatory compounds such as minocycline (Agrawal et al, 2011) and the NFκB inhibitor, caffeic acid phenethyl ester (CAPE) have been shown to reduce alcohol consumption (Harris and Blednov, 2013), it would be intriguing to evaluate the effects of IL-10 administration on EtOH consumption and preference.…”

Section: Discussionmentioning

confidence: 99%

Role of interleukin-10 (IL-10) in regulation of GABAergic transmission and acute response to ethanol

et al. 2016

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Mounting evidence indicates that ethanol (EtOH) exposure activates neuroimmune signaling. Alterations in pro-inflammatory cytokines after acute and chronic EtOH exposure have been heavily investigated. In contrast, little is known about the regulation of neurotransmission and/or modulation by anti-inflammatory cytokines in the brain after an acute EtOH exposure. Recent evidence suggests that interleukin-10 (IL-10), an anti-inflammatory cytokine, is upregulated during withdrawal from chronic EtOH exposure. In the present study, we show that IL-10 is increased early (1 h) after a single intoxicating dose of EtOH (5 g/kg, intragastric) in Sprague Dawley rats. We also show that IL-10 rapidly regulates GABAergic transmission in dentate gyrus neurons. In brain slice recordings, IL-10 application dose-dependently decreases miniature inhibitory postsynaptic current (mIPSC) area and frequency, and decreases the magnitude of the picrotoxin sensitive tonic current (Itonic), indicating both pre- and postsynaptic mechanisms. A PI3K inhibitor LY294002 (but not the negative control LY303511) ablated the inhibitory effects of IL-10 on mIPSC area and Itonic, but not on mIPSC frequency, indicating the involvement of PI3K in postsynaptic effects of IL-10 on GABAergic transmission. Lastly, we also identify a novel neurobehavioral regulation of EtOH sensitivity by IL-10, whereby IL-10 attenuates acute EtOH-induced hypnosis. These results suggest that EtOH causes an early release of IL-10 in the brain, which may contribute to neuronal hyperexcitability as well as disturbed sleep seen after binge exposure to EtOH. These results also identify IL-10 signaling as a potential therapeutic target in alcohol-use disorders and other CNS disorders where GABAergic transmission is altered.

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“…Most model parameter values used here are taken from references 69, 71, and 76 and are given in Table 1. We used semiquantitative studies from the literature on STAT1 (88, 89), STAT3 (90)(91)(92)(93), and NF-B (107) to specify ranges for parameters related to the macrophage polarization ratio introduced in this work (see Table 1 for details). Additionally, we relied on uncertainty analysis (UA) and sensitivity analysis (SA) techniques.…”

Section: Models Of Stat1 Stat3 and Nf-b Dynamicsmentioning

confidence: 99%

Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

et al. 2015

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c Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), induces formation of granulomas, structures in which immune cells and bacteria colocalize. Macrophages are among the most abundant cell types in granulomas and have been shown to serve as both critical bactericidal cells and targets for M. tuberculosis infection and proliferation throughout the course of infection. Very little is known about how these processes are regulated, what controls macrophage microenvironment-specific polarization and plasticity, or why some granulomas control bacteria and others permit bacterial dissemination. We take a computational-biology approach to investigate mechanisms that drive macrophage polarization, function, and bacterial control in granulomas. We define a "macrophage polarization ratio" as a metric to understand how cytokine signaling translates into polarization of single macrophages in a granuloma, which in turn modulates cellular functions, including antimicrobial activity and cytokine production. Ultimately, we extend this macrophage ratio to the tissue scale and define a "granuloma polarization ratio" describing mean polarization measures for entire granulomas. Here we coupled experimental data from nonhuman primate TB granulomas to our computational model, and we predict two novel and testable hypotheses regarding macrophage profiles in TB outcomes. First, the temporal dynamics of granuloma polarization ratios are predictive of granuloma outcome. Second, stable necrotic granulomas with low CFU counts and limited inflammation are characterized by short NF-B signal activation intervals. These results suggest that the dynamics of NF-B signaling is a viable therapeutic target to promote M 1 polarization early during infection and to improve outcome.

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Identification and characterization of a human IL-10 receptor antagonist

Cited by 15 publications

References 15 publications

IL10, TGF Beta1, and IFN Gamma Modulate Intracellular Signaling Pathways and Cytokine Production to Control Toxoplasma gondii Infection in BeWo Trophoblast Cells1

IL10, TGF Beta1, and IFN Gamma Modulate Intracellular Signaling Pathways and Cytokine Production to Control Toxoplasma gondii Infection in BeWo Trophoblast Cells1

Role of interleukin-10 (IL-10) in regulation of GABAergic transmission and acute response to ethanol

Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection

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