Single-Cell, Phosphoepitope-Specific Analysis Demonstrates Cell Type- and Pathway-Specific Dysregulation of Jak/STAT and MAPK Signaling Associated with In Vivo Human Immunodeficiency Virus Type 1 Infection

Systemic juvenile idiopathic arthritis (sJIA) is characterized by systemic inflammation and arthritis. Monocytes are implicated in sJIA pathogenesis, but their role in disease is unclear. The response of sJIA monocytes to IFN may be dysregulated. We examined intracellular signaling in response to IFN type I (IFNα) and type II (IFNγ) in monocytes during sJIA activity and quiescence, in 2 patient groups. Independent of disease activity, monocytes from Group 1 (collected between 2002-2009) showed defective STAT1 phosphorylation downstream of IFNs, and expressed higher transcript levels of SOCS1, an inhibitor of IFN signaling. In the Group 2 (collected between 2011-2014), monocytes of patients with recent disease onset were IFNγ hyporesponsive, but in treated, quiescent subjects, monocytes were hyperresponsive to IFNγ. Recent changes in medication in sJIA may alter the IFN hyporesponsiveness. Impaired IFN/pSTAT1 signaling is consistent with skewing of sJIA monocytes away from an M1 phenotype and may contribute to disease pathology.

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“…Phospho-flow [19, 23] was performed as detailed below. PBMC were thawed and rested for 90 min in RPMI with 5% (HI) human AB serum.…”

Section: Patients Materials and Methodsmentioning

confidence: 99%

Altered signaling in systemic juvenile idiopathic arthritis monocytes

Macaubas

Wong

Zhang

et al. 2016

Clinical Immunology

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“…The difference in p38 MAPK activation may result in the differential cytotoxicity of cisplatin [12]. To study the effect of complexes 1, 2, and cisplatin on the activation of MAPKs, changes of ERK1/2 and p38 MAPK phosphorylation in COC1 cells were investigated using instracellular staining [36]. Specific inhibitor U0126 and stimulator PMA of phospho-ERK1/2 were used as negative and positive controls, which induced a decrease and an increase of ERK1/2 phosphorylation, respectively [37].…”

Section: Arrest Of Cell Cyclementioning

confidence: 99%

Cellular and biomolecular responses of human ovarian cancer cells to cytostatic dinuclear platinum(II) complexes

et al. 2010

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Polynuclear platinum(II) complexes represent a class of potential anticancer agents that have shown promising pharmacological properties in preclinical studies. The nature of cellular responses induced by these complexes, however, is poorly understood. In this research, the cellular responses of human ovarian cancer COC1 cells to dinuclear platinum(II) complexes {[cis-Pt(NH₃)₂Cl]₂L¹}(NO₃)₂ (1) and {[cis-Pt(NH₃)₂Cl]₂L²}(NO₃)₂ (2) (L¹ = α,α'-diamino-p-xylene, L² = 4,4'-methylenedianiline) has been studied using cisplatin as a reference. The effect of platinum complexes on the proliferation, death mode, mitochondrial membrane potential, and cell cycle progression has been examined by MTT assay and flow cytometry. The activation of cell cycle checkpoint kinases (CHK1/2), extracellular signal-regulated kinases (ERK1/2), and p38 mitogen-activated protein kinase (p38 MAPK) of the cells by the complexes has also been analyzed using phospho-specific flow cytometry. Complex 1 is more cytotoxic than complex 2 and cisplatin at most concentrations; complex 2 and cisplatin are comparably cytotoxic. These complexes kill the cells through an apoptotic or apoptosis-like pathway characterized by exposure of phosphatidylserine and dissipation of mitochondrial membrane potential. Complex 1 shows the strongest inductive effect on the morphological changes of the cells, followed by cisplatin and complex 2. Complexes 1 and 2 arrest the cell cycle in G2 or M phase, while cisplatin arrests the cell cycle in S phase. The influence of these complexes on CHK1/2, ERK1/2, and p38 MAPK varies with the dose of the drugs or reaction time. Activation of phospho-ERK1/2 and phospho-p38 MAPK by these complexes is closely related to the cytostatic activity. The results demonstrate that dinuclear platinum(II) complexes can induce some cellular responses different from those caused by cisplatin.

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“…For example, in cells infected with an attenuated adenoviral vector (Adv), Adv infection saturated Akt pro-survival signaling and blocked insulin-mediated anti-apoptotic signaling in cells treated with TNF, causing apoptosis in host cells (2). In another study comparing HIV-1 infected and uninfected monocytes, HIV-1 infection significantly changed monocyte activation in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) via down-regulation of Jak/STAT signaling but enhancement of MAPK signaling (22), resulting in defective antigen presentation. These studies focused on a single pathway, however the extent of viral-mediated changes could be more fully understood by measuring changes across multiple pathways in the network and using computational methods to analyze the experimental data.…”

Section: Systems Approaches To Analyze Viral-mediated Changes To Signmentioning

confidence: 99%

Systems biology of virus-host signaling network interactions

Xue¹,

Miller‐Jensen²

2012

BMB Reports

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Viruses have evolved to manipulate the host cell machinery for virus propagation, in part by interfering with the host cellular signaling network. Molecular studies of individual pathways have uncovered many viral host-protein targets; however, it is difficult to predict how viral perturbations will affect the signaling network as a whole. Systems biology approaches rely on multivariate, context-dependent measurements and computational analysis to elucidate how viral infection alters host cell signaling at a network level. Here we describe recent advances in systems analyses of signaling networks in both viral and non-viral biological contexts. These approaches have the potential to uncover virus-mediated changes to host signaling networks, suggest new therapeutic strategies, and assess how cell-to-cell variability affects host responses to infection. We argue that systems approaches will both improve understanding of how individual virus-host protein interactions fit into the progression of viral pathogenesis and help to identify novel therapeutic targets. [BMB reports 2012; 45(4): 213-220]

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Single-Cell, Phosphoepitope-Specific Analysis Demonstrates Cell Type- and Pathway-Specific Dysregulation of Jak/STAT and MAPK Signaling Associated with In Vivo Human Immunodeficiency Virus Type 1 Infection

Cited by 24 publications

References 45 publications

Altered signaling in systemic juvenile idiopathic arthritis monocytes

Altered signaling in systemic juvenile idiopathic arthritis monocytes

Cellular and biomolecular responses of human ovarian cancer cells to cytostatic dinuclear platinum(II) complexes

Systems biology of virus-host signaling network interactions

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