TNF-blocking therapies: an alternative mode of action?

Choo-Kang, Brian; Hutchison, Sharon; Nickdel, Mohammad B.; Bundick, R. V.; Leishman, Andrew J.; Brewer, James M.; McInnes, Iain B.; Garside, Paul

doi:10.1016/j.it.2005.07.007

Cited by 36 publications

(32 citation statements)

References 49 publications

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“…TNF␣ is a major MC product (42) and is considered to act at the apex of proinflammatory pathways in inflammatory bowel disease (43)(44)(45) and to promote cancer (46). Here, we show that MC produce TNF␣ and require this cytokine for their expansion and differentiation ex vivo.…”

Section: Discussionmentioning

confidence: 70%

Mast cells are an essential hematopoietic component for polyp development

Gounaris

Erdman

Restaino

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

224

252

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It is generally agreed that most colon cancers develop from adenomatous polyps, and it is this fact on which screening strategies are based. Although there is overwhelming evidence to link intrinsic genetic lesions with the formation of these preneoplastic lesions, recent data suggest that the tumor stromal environment also plays an essential role in this disease. In particular, it has been suggested that CD34 ؉ immature myeloid precursor cells are required for tumor development and invasion. Here we have used mice conditional for the stabilization of ␤-catenin or defective for the adenomatous polyposis coli (APC) gene to reinvestigated the identity and importance of tumor-infiltrating hematopoietic cells in polyposis. We show that, from the onset, polyps are infiltrated with proinflammatory mast cells (MC) and their precursors. Depletion of MC either pharmacologically or through the generation of chimeric mice with genetic lesions in MC development leads to a profound remission of existing polyps. Our data suggest that MC are an essential hematopoietic component for preneoplastic polyp development and are a novel target for therapeutic intervention.cancer ͉ inflammation ͉ polyposis ͉ TNF␣

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Section: Discussionmentioning

confidence: 70%

Mast cells are an essential hematopoietic component for polyp development

Gounaris

Erdman

Restaino

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

224

252

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“…This points to a novel mechanism of action of infliximab in this condition, i.e., the amelioration of mucosal inflammation through the disruption of TNF-␣-dependent CD40/CD40L-mediated cognate interactions between the intestinal microcirculation and circulating T cells. This mechanism should be added to the growing list of alternative modes of actions of anti-TNF-␣ therapies that may better explain their immunomodulatory action besides direct neutralization of TNF-␣ and T cell killing (57).…”

Section: Discussionmentioning

confidence: 99%

TNF-α Blockade Down-Regulates the CD40/CD40L Pathway in the Mucosal Microcirculation: A Novel Anti-Inflammatory Mechanism of Infliximab in Crohn’s Disease

Danese¹,

Sans

Scaldaferri³

et al. 2006

The Journal of Immunology

154

101

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The CD40/CD40 ligand (CD40L) pathway is involved in Crohn’s disease (CD) pathogenesis. In the patients’ circulation, soluble CD40L (sCD40L) levels are elevated and surface CD40L is increased in platelets and T cells, whereas in the intestine CD40 is overexpressed in the microvasculature and CD40L in platelets and T cells. The therapeutic effects of infliximab in CD are attributed to its systemic anti-TNF-α action, but because TNF-α modulates both CD40 and CD40L, we investigated whether infliximab affects the CD40/CD40L pathway in the intestine. Eighteen CD patients were evaluated before and after infliximab therapy. Plasma sCD40L was measured by ELISA and platelet and peripheral blood T cell (PBT) CD40L expression by flow cytometry. Microvascular CD40 and VCAM-1 expression were assessed in mucosal biopsies by immunohistochemistry and by flow cytometry in human intestinal microvascular endothelial cells (HIMEC). Cell cultures were performed in the presence and absence of infliximab. Infliximab treatment significantly reduced plasma sCD40L levels and eliminated CD40 and VCAM-1 from mucosal microvessels. In vitro infliximab prevented TNF-α-induced CD40 and VCAM-1 expression by HIMEC, and reduced PBT, but not platelet, surface CD40L expression and sCD40L release. In addition, infliximab decreased T cell-induced VCAM-1 expression in HIMEC by down-regulating CD40L in T cells and promoting T cells apoptosis. These findings point to a novel mechanism of action of infliximab, i.e., the disruption of CD40/CD40L-dependent cognate interactions between intestinal microvessels and T cells. Thus, in addition to neutralizing TNF-α and inducing T cell death, the therapeutic effects of infliximab in CD appear to be also mediated by inhibition of vascular inflammation in the gut.

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“…S1A). Serum levels of TNF, a main causal factor of sepsis and endotoxemia (10)(11)(12)(13)(14)(15), had the peak at 1 h after LPS treatment to the same levels in WT and Rag2 −/− mice (Fig. S1A).…”

Section: T Cells Have a Protective Role In Lps Endotoxemia By Down-mentioning

confidence: 91%

T cells down-regulate macrophage TNF production by IRAK1-mediated IL-10 expression and control innate hyperinflammation

Inoue¹,

Arikawa²,

Chen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Endotoxemia is caused by excessive inflammation, but the immune system has various mechanisms to avoid collateral organ damage in endotoxemia. A handful of reports have shown that innate immune responses are suppressed by the adaptive immune system. However, the molecular mechanism by which adaptive immune cells suppress innate inflammatory responses is not clear. Here, we report that T cells are shown to interact with macrophages at the early stage of enodotoxemia and to prolong survival of mice through controlling TNF and IL-10 levels by macrophage CD40 stimulation. The cross-talk between CD40 and toll-like receptor (TLR4) signaling first mediates IL-1 receptor-associated kinase 1 (IRAK1) nuclear translocation and its binding to the IL-10 gene promoter in macrophages, without interfering with the NFκB pathway. IL-10 is then detected by macrophages in an autocrine fashion to destabilize Tnfa mRNA. To induce IRAK1-mediated IL-10 expression, signals from both CD40 and TLR4 are essential. CD40 signaling induces IRAK1 sumoylation in the presence of TNF receptor-associated factor 2 (TRAF2) and intracellular isoform of osteopontin (iOPN) whereas TLR4 signaling provides IFN regulatory factor 5 (IRF5) as a chaperone for sumoylated IRAK1 nuclear translocation. Interaction of T cells with macrophages was observed in the spleen in vivo after endotoxemia induction with LPS injection. Our study demonstrates a mechanistic basis for the immunosuppressive role of macrophage CD40 in LPS endotoxemia.OPN | CD40L | CD154 | simultaneous stimulation | T cell migration

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TNF-blocking therapies: an alternative mode of action?

Cited by 36 publications

References 49 publications

Mast cells are an essential hematopoietic component for polyp development

Mast cells are an essential hematopoietic component for polyp development

TNF-α Blockade Down-Regulates the CD40/CD40L Pathway in the Mucosal Microcirculation: A Novel Anti-Inflammatory Mechanism of Infliximab in Crohn’s Disease

T cells down-regulate macrophage TNF production by IRAK1-mediated IL-10 expression and control innate hyperinflammation

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