Enhanced Activity of Akt in Teff Cells From Children With Lupus Nephritis Is Associated With Reduced Induction of Tumor Necrosis Factor Receptor–Associated Factor 6 and Increased OX40 Expression

Kshirsagar, Sudhir; Binder, Elisabeth B.; Riedl, Magdalena; Wechselberger, Gottfried; Steichen, Elisabeth; Edelbauer, Monika

doi:10.1002/art.38089

Cited by 18 publications

(23 citation statements)

References 46 publications

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“…Consistent with observations from conditions where there is [97][98][99][100][101][102][103] Increased endothelial expression in kidney biopsies from lupus nephritis patients with the appearance of glomerular positivity [97] OX40 on infiltrating perivascular leucocytes in lupus nephritis [97] Increased peripheral sOX40L, with further elevations in those with nephritis [99] More activated phenotype with increased PI3/Akt activation (see Fig. 4…”

Section: Ox40 Is Upregulated On Peripheral Circulating Lymphocytes Insupporting

confidence: 89%

“…OX40L is trimeric and each trimer associates with three OX40 molecules. The signaling complex alters transcription through multiple pathways: a signaling complex involving TNF receptor associated factor 2 and 6, and possibly TRAF5, and IKKα, IKKβ, IKKγ is formed, IκB is phosphorylated and degraded and the NFκB sub-unit RelA, along with p50 is then able to enter the nucleus [167,168,68]; in a TRAF6-dependent process, IKKα acts to permit RelB nuclear entry [55]; the OX40 signaling complex phosphorylates STAT5 permitting nuclear entry [61]; OX40 permits the intracellular entry of calcium, this then activates calcineurin via calmodulin resulting in the dephosphorylation and nuclear entry of NFAT [8]; PI3K complexed to activated OX40 increases phosphorylation of AKT (also known as a PKB) in a PDKdependent manner, this in turn amplifies signaling through the IKK complex [100]. The NFAT and PI3K pathways amplify signals from antigen-stimulated T cell receptors.…”

Section: Ox40 and Ox40 Ligand Aberrations In Transgenic Micementioning

confidence: 99%

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OX40, OX40L and Autoimmunity: a Comprehensive Review

Webb

Hirschfield

Lane

2015

Clinic Rev Allerg Immunol

215

159

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The tumour necrosis factor receptor OX40 (CD134) is activated by its cognate ligand OX40L (CD134L, CD252) and functions as a T cell co-stimulatory molecule. OX40-OX40L interactions have been proposed as a potential therapeutic target for treating autoimmunity. OX40 is expressed on activated T cells, and in the mouse at rest on regulatory T cells (Treg). OX40L is found on antigen-presenting cells, activated T cells and others including lymphoid tissue inducer cells, some endothelia and mast cells. Expression of both molecules is increased after antigen presentation occurs and also in response to multiple other pro-inflammatory factors including CD28 ligation, CD40L ligation and interferon-gamma signaling. Their interactions promote T cell survival, promote an effector T cell phenotype, promote T cell memory, tend to reduce regulatory function, increase effector cytokine production and enhance cell mobility. In some circumstances, OX40 agonism may be associated with increased tolerance, although timing with respect to antigenic stimulus is important. Further, recent work has suggested that OX40L blockade may be more effective than OX40 blockade in reducing autoimmunity. This article reviews the expression of OX40 and OX40L in health, the effects of their interactions and insights from their under- or over-expression. We then review OX40 and OX40L expression in human autoimmune disease, identified associations of variations in their genes (TNFRSF4 and TNFSF4, respectively) with autoimmunity, and data from animal models of human diseases. A rationale for blocking OX40-OX40L interaction in human autoimmunity is then presented along with commentary on the one trial of OX40L blockade in human disease conducted to date. Finally, we discuss potential problems with clinical use of OX40-OX40L directed pharmacotherapy.

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Section: Ox40 Is Upregulated On Peripheral Circulating Lymphocytes Insupporting

confidence: 89%

Section: Ox40 and Ox40 Ligand Aberrations In Transgenic Micementioning

confidence: 99%

OX40, OX40L and Autoimmunity: a Comprehensive Review

Webb

Hirschfield

Lane

2015

Clinic Rev Allerg Immunol

215

159

View full text Add to dashboard Cite

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“…+ T cell population functionally defective for effector cell inhibition and for production of proinflammatory cytokines such as IL-17 (68 Analysis of the effect of PI3Kd inhibition on autoantibody and cytokine production in MRL/lpr mice showed that all IgG isotypes were moderately decreased in serum, with a greater reduction in the Th1-IgG2b isotype. Most Th1 and Th2 cytokines were barely detectable in serum; nonetheless, in vitro stimulation of T cells showed that GS-9829 treatment reduced Th1 and Th2 cytokines.…”

Section: Foxp3mentioning

confidence: 99%

Inhibition of PI3Kδ Reduces Kidney Infiltration by Macrophages and Ameliorates Systemic Lupus in the Mouse

Suárez‐Fueyo

Rojas

Cariaga

et al. 2014

The Journal of Immunology

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Systemic lupus erythematosus (SLE) is a human chronic inflammatory disease generated and maintained throughout life by autoreactive T and B cells. Class I phosphoinositide 3-kinases (PI3K) are heterodimers composed of a regulatory and a catalytic subunit that catalyze phosphoinositide-3,4,5-P3 formation and regulate cell survival, migration, and division. Activity of the PI3Kδ isoform is enhanced in human SLE patient PBLs. In this study, we analyzed the effect of inhibiting PI3Kδ in MRL/lpr mice, a model of human SLE. We found that PI3Kδ inhibition ameliorated lupus progression. Treatment of these mice with a PI3Kδ inhibitor reduced the excessive numbers of CD4+ effector/memory cells and B cells. In addition, this treatment reduced serum TNF-α levels and the number of macrophages infiltrating the kidney. Expression of inactive PI3Kδ, but not deletion of the other hematopoietic isoform PI3Kγ, reduced the ability of macrophages to cross the basement membrane, a process required to infiltrate the kidney, explaining MRL/lpr mice improvement by pharmacologic inhibition of PI3Kδ. The observations that p110δ inhibitor prolonged mouse life span, reduced disease symptoms, and showed no obvious secondary effects indicates that PI3Kδ is a promising target for SLE.

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“…Interestingly, the PI3K/Akt pathway has been reported to be involved in the phosphorylation of Stat3 (29,50). We previously demonstrated that Akt is hyperactivated in effector T cells from lupus patients (30). Hyperactivation of Akt may thus further enhance Stat3 activity.…”

Section: Discussionmentioning

confidence: 93%

“…other factors (37). We previously demonstrated that Akt is overactivated in CD4 + CD45RA 2 Foxp3 2 and Foxp3 low T cells from children with LN (30). In this study, we further assessed the activation status and function of Akt in IL-17-producing CD4 + CD45RA 2 Foxp3 2 and Foxp3 low T cells from children with LN.…”

Section: Cells In Pediatric Patients With Lnmentioning

confidence: 87%

Akt-Dependent Enhanced Migratory Capacity of Th17 Cells from Children with Lupus Nephritis

Kshirsagar

Riedl

Billing

et al. 2014

The Journal of Immunology

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Th17 cells infiltrate the kidneys of patients with lupus nephritis (LN) and are critical for the pathogenesis of this disease. In this study, we show that enhanced activity of Stat3 in CD4+CD45RA−Foxp3− and Foxp3low effector T cells from children with LN correlates with increased frequencies of IL-17–producing cells within these T cell populations. The levels of retinoic acid-related orphan receptor c and IL-17 mRNA are significantly higher in PBMCs from children with LN than in those from controls. Mammalian target of rapamycin inhibition by rapamycin reduces both Stat3 activation in effector T cells and the frequency of IL-17–producing T cells in lupus patients. Complement factor C5a slightly increases the expression of IL-17 and induces activation of Akt in anti-CD3–activated lupus effector T cells. Th17 cells from children with LN exhibit high Akt activity and enhanced migratory capacity. Inhibition of the Akt signaling pathway significantly decreases Th17 cell migration. These findings indicate that the Akt signaling pathway plays a significant role in the migratory activity of Th17 cells from children with LN and suggest that therapeutic modulation of the Akt activity may inhibit Th17 cell trafficking to sites of inflammation and thus suppress chronic inflammatory processes in children with LN.

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Enhanced Activity of Akt in Teff Cells From Children With Lupus Nephritis Is Associated With Reduced Induction of Tumor Necrosis Factor Receptor–Associated Factor 6 and Increased OX40 Expression

Abstract: Objective. The breakdown of peripheral tolerance mechanisms is central to the pathogenesis of systemic lupus erythematosus (SLE).

Cited by 18 publications

References 46 publications

OX40, OX40L and Autoimmunity: a Comprehensive Review

OX40, OX40L and Autoimmunity: a Comprehensive Review

Inhibition of PI3Kδ Reduces Kidney Infiltration by Macrophages and Ameliorates Systemic Lupus in the Mouse

Akt-Dependent Enhanced Migratory Capacity of Th17 Cells from Children with Lupus Nephritis

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