Inhibition of IL-12 Production in Human Monocyte-Derived Macrophages by TNF

Ma, Xiaojing; Sun, Junwei; Papasavvas, Emmanouil; Riemann, Helge; Robertson, Susan; Marshall, Jason D.; Bailer, Robert T.; Moore, A. R.; Donnelly, Raymond P.; Trinchieri, Giorgio; Montaner, Luis J.

doi:10.4049/jimmunol.164.4.1722

Cited by 94 publications

(81 citation statements)

References 47 publications

(30 reference statements)

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“…However, TNF-α and IL-6 are also involved in directing the generation of the T H 1 response, but unlike IL-12, they are indirectly involved in suppressing T H 1 responses. TNF-α inhibits IL-12 and the subsequent production of IFN-γ, limiting IL-12 through both IL-10 dependent and independent means [23,31,48]. IL-6 suppresses T H 1 development by boosting the T H 2 activity of IL-4 and interfering with IFN-γ signaling [13], and redirecting T helper responses [24].…”

Section: Discussionmentioning

confidence: 99%

Lactoferrin modulation of IL-12 and IL-10 response from activated murine leukocytes

Hwang¹,

Wilk²,

Bangale³

et al. 2007

Med Microbiol Immunol

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Lactoferrin possesses a wide range of immunomodulatory activities, including promotion of the delayed type hypersensitivity response (DTH) towards BCG (Bacillus Calmette Guerin) antigens. Addition of Lactoferrin as an adjuvant to the BCG vaccine was previously demonstrated to augment protection against subsequent mycobacterial challenge, with concomitant development of a strong T cell helper type 1 (T H 1) immunity. Because generation of T H 1 immunity is in large part dependent on the balance of monocytic pro-and anti-inflammatory cytokines, the effect of Lactoferrin on leukocytes was investigated. Lactoferrin enhanced proinflammatory responses in a dose-dependant manner from splenocyte and adherent (F4/80 + ) splenocyte populations, bone marrow derived monocytes (BMM), and J774A.1 cultured cells. In all scenarios tested, Lactoferrin induced a strong increase in the ratio of IL-12:IL-10 production from LPS stimulated cells. Examination of Lactoferrin effects on BCG infected J774A.1 cells and on BMM revealed similar immunomodulatory effects, with particularly strong increase in IL-12 production. Furthermore, immunization of mice with BCG admixed with Lactoferrin led to increased generation of CD4+ cells expressing IFN-γ upon restimulation with BCG antigens. These results provide molecular evidence to support the role of Lactoferrin as an adjuvant candidate to augment development of DTH response to vaccine antigens.

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Section: Discussionmentioning

confidence: 99%

Lactoferrin modulation of IL-12 and IL-10 response from activated murine leukocytes

Hwang¹,

Wilk²,

Bangale³

et al. 2007

Med Microbiol Immunol

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“…5). While the expression of IL-1b mRNA by AMs was increased in coculture (*2.8-fold; p = 0.017), the expression of IL-12b-another marker associated with inflammation 70 -was reduced (*3.3-fold; p = 0.024) upon coculture with OACs (Fig. 5A).…”

Section: D System To Study Effects Of Osteoarthritic Inflammationmentioning

confidence: 99%

A Three-Dimensional Chondrocyte-Macrophage Coculture System to Probe Inflammation in Experimental Osteoarthritis

Samavedi

Díaz‐Rodríguez

Erndt-Marino

et al. 2017

Tissue Engineering Part A

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The goal of the present study was to develop a fully three-dimensional (3D) coculture system that would allow for systematic evaluation of the interplay between activated macrophages (AMs) and chondrocytes in osteoarthritic disease progression and treatment. Toward this end, our coculture system was first validated against existing in vitro osteoarthritis models, which have generally cultured healthy normal chondrocytes (NCs)-in two-dimensional (2D) or 3D-with proinflammatory AMs in 2D. In this work, NCs and AMs were both encapsulated within poly(ethylene glycol) diacrylate hydrogels to mimic the native 3D environments of both cell types within the osteoarthritic joint. As with previous studies, increases in matrix metalloproteinases (MMPs) and proinflammatory cytokines associated with the early stages of osteoarthritis were observed during NC-AM coculture, as were decreases in protein-level Aggrecan and collagen II. Thereafter, the coculture system was extended to osteoarthritic chondrocytes (OACs) and AMs to evaluate the potential effects of AMs on pre-existing osteoarthritic phenotypes. OACs in coculture with AMs expressed significantly higher levels of MMP-1, MMP-3, MMP-9, MMP-13, IL-1b, TNF-a, IL-6, IL-8, and IFN-g compared to OACs in mono-culture, indicating that proinflammatory macrophages may intensify the abnormal matrix degradation and cytokine secretion already associated with OACs. Likewise, AMs cocultured with OACs expressed significantly more IL-1b and VEGF-A compared to AM mono-culture controls, suggesting that OACs may intensify abnormal macrophage activation. Finally, OACs cultured in the presence of nonactivated macrophages produced lower levels of MMP-9 and proinflammatory cytokines IL-1b, TNF-a, and IFN-g compared to OACs in the OAC-AM system, results that are consistent with anti-inflammatory agents temporarily reducing certain OA symptoms. In summary, the 3D coculture system developed herein captures several key features of inflammatory OA and may prove useful in future screening of therapeutic agents and/or assessment of disease progression mechanisms.

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“…TNF-␣ recently has been shown to exert an inhibitory effect on IL-12 production (39,40). Although itself a target of inhibition during endotoxin tolerance, TNF-␣ is produced earlier than IL-12 and thus might be of mechanistic importance in endotoxin tolerance-driven inhibition of IL-12 (22).…”

Section: Down-modulation Of Il-12 In Lps-tolerized Mice Does Not Requmentioning

confidence: 99%

IL-12 Suppression During Experimental Endotoxin Tolerance: Dendritic Cell Loss and Macrophage Hyporesponsiveness

Wysocka

Robertson

Riemann

et al. 2001

The Journal of Immunology

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126

122

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Endotoxin tolerance, the transient, secondary down-regulation of a subset of endotoxin-driven responses after exposure to bacterial products, is thought to be an adaptive response providing protection from pathological hyperactivation of the innate immune system during bacterial infection. However, although protecting from the development of sepsis, endotoxin tolerance also can lead to fatal blunting of immunological responses to subsequent infections in survivors of septic shock. Despite considerable experimental effort aimed at characterizing the molecular mechanisms responsible for a variety of endotoxin tolerance-related phenomena, no consensus has been achieved yet. IL-12 is a macrophage- and dendritic cell (DC)-derived cytokine that plays a key role in pathological responses to endotoxin as well as in the induction of protective responses to pathogens. It recently has been shown that IL-12 production is suppressed in endotoxin tolerance, providing a likely partial mechanism for the increased risk of secondary infections in sepsis survivors. We examined the development of IL-12 suppression during endotoxin tolerance in mice. Decreased IL-12 production in vivo is clearly multifactorial, involving both loss of CD11chigh DCs as well as alterations in the responsiveness of macrophages and remaining splenic DCs. We find no demonstrable mechanistic role for B or T lymphocytes, the soluble mediators IL-10, TNF-α, IFN-αβ, or nitric oxide, or the NF-κB family members p50, p52, or RelB.

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Inhibition of IL-12 Production in Human Monocyte-Derived Macrophages by TNF

Cited by 94 publications

References 47 publications

Lactoferrin modulation of IL-12 and IL-10 response from activated murine leukocytes

Lactoferrin modulation of IL-12 and IL-10 response from activated murine leukocytes

A Three-Dimensional Chondrocyte-Macrophage Coculture System to Probe Inflammation in Experimental Osteoarthritis

IL-12 Suppression During Experimental Endotoxin Tolerance: Dendritic Cell Loss and Macrophage Hyporesponsiveness

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