Effects of Infliximab on Apoptosis and Reverse Signaling of Monocytes from Healthy Individuals and Patients with Crohn’s Disease

Ringheanu, Mihaela; Daum, Fredric; Markowitz, James; Levine, Jeremiah; Katz, Seymour; Lin, Xingyu; Silver, Jack

doi:10.1097/00054725-200411000-00015

Cited by 68 publications

(47 citation statements)

References 30 publications

(36 reference statements)

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“…For example, one study found no increase in the number of apoptotic cells when PBMCs isolated from patients with CD were cultured overnight in the presence of INF [48]. In fact, the researchers believed that these cells were stabilized against apoptosis.…”

Section: Effect On Apoptosismentioning

confidence: 99%

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TNFα blockade in human diseases: Mechanisms and future directions

Wong

Ziring

Korin

et al. 2008

Clinical Immunology

260

162

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Tumor necrosis factor-alpha (TNFα) antagonists have shown remarkable efficacy in a variety of immune-mediated inflammatory diseases (IMIDs). Therapeutic scope and limitations of these agents are reviewed in a recently published article in the Journal. In spite of their therapeutic popularity, little is known about their modes of action in vivo and factors that limit their scope of therapeutic use. Intriguingly, while all TNFα antagonists including blocking antibodies and soluble receptors are effective in certain IMIDs, only anti-TNFα antibodies are effective in other IMIDs. Early efforts at understanding how TNFα antagonists act in IMIDs centered on their ability to neutralize soluble TNFα or to block TNF receptors from binding to their ligands. Subsequent studies suggested a role of complement-mediated lysis or antibody-dependent cell cytotoxicity in their therapeutic effects. More recent models postulate that TNFα blockers may act by affecting intracellular signaling, with the end result being a hastened cell cycle arrest, apoptosis, suppression of cytokine production, or improved Treg cell function. TNFα antagonists can also modulate the functions of myofibroblasts and osteoclasts, which might explain how TNFα antagonists reduce tissue damage in chronic IMIDs. Focusing on the human therapeutic experience, this analytical review will review the biology of mechanisms of action, the limiting factors contributing to disease restriction in therapeutic efficacy, and the mechanism and frequency of treatment-limiting adverse responses of TNFα antagonists. It is hoped that the overview will address the needs of clinicians to decide on optimal use, spur clinical innovation, and incite translational researchers to set priorities for in vivo human investigations.

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Section: Effect On Apoptosismentioning

confidence: 99%

“…1). Ringheanu et al [48] found that INF induced "reverse signaling" in isolated PBMCs in vitro to downregulate the production of inflammatory cytokines. They showed that monocytes produced less TNFα after they had been exposed to LPS or SEA when cultured with INF.…”

Section: Effect On Cytokine Productionmentioning

confidence: 99%

TNFα blockade in human diseases: Mechanisms and future directions

Wong

Ziring

Korin

et al. 2008

Clinical Immunology

260

162

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“…It neutralizes TNF-a, 15 and induces apoptosis of activated T cells and lymphocytes in the lamina propria thereby reducing the levels of IL-1, IL-6, IL-18 and IFN-g both in vivo [16][17][18] and in vitro. [19][20][21] In the present investigation we determined the changes in the levels and gene expression of the adhesion molecules PECAM-1, ICAM-1 and vascular cell adhesion molecule-1 (VCAM)-1 in two different in vitro models of inflammation, phytohaemagglutinin (PHA)-and LPS-stimulated PBLs, and we defined which adhesion molecules are restored by infliximab treatment in activated leukocytes. In addition, the expression profiles of the genes encoding human PECAM-1 and ICAM-1 in a promonocytic cell line U-937 (a model used to study macrophages biological functions) in response to treatment with PHA and LPS have been defined and using these two models the effect of the anti-TNF-a antibody, infliximab, on PECAM-1, ICAM-1 and VCAM-1 gene expression was determined.…”

mentioning

confidence: 99%

The anti-TNF-α antibody infliximab indirectly regulates PECAM-1 gene expression in two models of in vitro blood cell activation

Moriconi

Malik

Amanzada

et al. 2012

Laboratory Investigation

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Chronic inflammatory bowel diseases can be successfully treated with antibodies against the acute phase mediator TNF-a. The process of activation and of extravasation of inflammatory cells from the blood into the 'stressed' tissue site is controlled by cytokines and chemokines, which attract leukocytes and by adhesion molecules, which mediate their attachment and transmigration toward the affected cell(s). The changes in the gene expression of adhesion molecules taking place in those cells before attachment have been less investigated. Changes of PECAM-1, ICAM-1 and vascular cell adhesion molecule-1 (VCAM-1) gene expression were studied in phytohaemagglutinin (PHA)-and lipolysaccharide (LPS)-treated human peripheral blood leukocytes (PBLs), granulocytes and the human monocyte cell line U-937. Cells were treated either with PHA or with LPS in the presence or absence of infliximab and incubated with TNF-a, IFN-g and/or transforming growth factor beta (TGF-b) and treated as above. Activation of PBLs by PHA or LPS treatment triggered a sharp upregulation of ICAM-1, VCAM-1 gene expression and a time-dependent downregulation of PECAM-1 gene expression reaching a minimum 4 h from start of the experiment. The anti-TNF-a antibody infliximab, by neutralizing TNF-a and IFN-g production, completely reversed PECAM-1 mRNA downregulation and ICAM-1 and VCAM-1 upregulation. Immunostaining of PBLs cytospins with antibodies against PECAM-1 and ICAM-1 confirmed RT-PCR and western blot results. PBLs IFN-g or TNF-a treatment downregulated PECAM-1 in parallel with the upregulation of ICAM-1 and VCAM-1 gene expression, whereas TGF-b upregulated PECAM-1-and downregulated ICAM-1 and VCAM-1 gene expression counteracting the effect of TNF-a or IFN-g. Similar results were obtained in human U937 cells and in granulocyte cultures by TNF-a or IFN-g treatment. Taken together, these results suggest that infliximab, blocking TNF-a and IFN-g production, exerts its anti-inflammatory effect through inhibiting downregulation of PECAM-1 gene expression and upregulation of ICAM-1 and VCAM-1 expression in leukocytes of the peripheral blood. These results also suggest that TGF-b may thus be of therapeutic importance as an anti-inflammatory agent.

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“…First, it is a TNF-␣ neutralizer, binding both monomeric and trimeric forms of this cytokine (32). Second, infliximab causes apoptosis of activated T cells and lamina propria lymphocytes (LPLs) (7,11,22,28,33,36,37). Its ability to induce apoptosis of monocytes is controversial as shown by conflicting in vitro data (22,28).…”

mentioning

confidence: 99%

“…Its ability to induce apoptosis of monocytes is controversial as shown by conflicting in vitro data (22,28). Similarly, monocyte counts decline with infliximab infusion in some studies (21,25) but not others (28). Third, infliximab alters cytokine secretion in the serum and lamina propria, decreasing IL-1, IL-6, IL-18, and IFN-␥ production (2,3,4,8,10,21,25,26,28).…”

mentioning

confidence: 99%

Infliximab and the TNF-α system

Ebert¹

2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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Infliximab, a chimeric monoclonal antibody against TNF-α, is efficacious in Crohn's disease (CD) and rheumatoid arthritis (RA). Its main mechanism of action is thought to be the induction of apoptosis. The present study evaluates in detail the effects of infliximab on the TNF-α system using peripheral blood monocytes and T cells as well as lamina propria lymphocytes from normal individuals and patients with CD, ulcerative colitis, and RA. Lymphocytes were studied in the resting state in the absence of strong stimuli that may obscure subtle findings. Infliximab did not change the numbers of viable cells. Rather, it caused monocytes to increase their release of soluble TNFR2, which serves to neutralize TNF-α, potentiating the action of infliximab. It reduced TNFR2 expression, thereby decreasing TNF-α responsiveness. These changes were due to upregulated production of TNFR2 rather than increased shedding. Infliximab did not cause rebound production of TNF-α transcripts that would counteract its effects. It specifically enhanced production of IL-10 but not proinflammatory cytokines secreted by leukocytes, thereby promoting an anti-inflammatory microenvironment. In addition, infliximab caused a rise in c-Jun amino-terminal kinase phosphorylation by monocytes. Thus infliximab manipulates the TNF-α system to promote its anti-TNF-α effects.

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Effects of Infliximab on Apoptosis and Reverse Signaling of Monocytes from Healthy Individuals and Patients with Crohn’s Disease

Abstract: Apoptosis of monocytes is not responsible for the therapeutic effects of infliximab. However, some of the therapeutic effects of infliximab may be caused by its ability to down-regulate proinflammatory cytokines production by monocytes exposed to bacterial antigens.

Cited by 68 publications

References 30 publications

TNFα blockade in human diseases: Mechanisms and future directions

TNFα blockade in human diseases: Mechanisms and future directions

The anti-TNF-α antibody infliximab indirectly regulates PECAM-1 gene expression in two models of in vitro blood cell activation

Infliximab and the TNF-α system

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