Lung Epithelial NF-<i>κ</i>B and Stat1 Signaling in Response to CD8<sup>+</sup>T Cell Antigen Recognition

Ramana, Chilakamarti V.; Chintapalli, Jyothi; Xu, Lumei; Alia, Christopher S.; Zhou, Jing; Bruder, Dunja; Enelow, Richard I.

doi:10.1089/jir.2006.26.318

Cited by 12 publications

(20 citation statements)

References 43 publications

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“…MCP-1 recruits immune cells to sites of tissue injury and infection, whereas IL-1␤ is a potent mediator of the inflammatory response. Induction of MCP-1 and IL-1␤ is induced largely or entirely through TNFR1 and is effected by activation of diverse signaling pathways and transcription factors (57)(58)(59)(60)(61)(62). Consistent with the pleiotropic mechanisms through which CCL2/MCP-1 and IL-1␤ can be induced, and the demonstration that c-Src and Jak2 are used by TNFR1 to engage diverse signaling pathways, we found that PP2 and AG490 each inhibited expression of these gene products.…”

Section: Discussionsupporting

confidence: 76%

Type 1 TNF Receptor Forms a Complex with and Uses Jak2 and c-Src to Selectively Engage Signaling Pathways That Regulate Transcription Factor Activity

Pincheira

Castro

Özeş

et al. 2008

The Journal of Immunology

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The type 1 TNFR (TNFR1) contains a death domain through which it interacts with other death-domain proteins to promote cellular responses. However, signaling through death-domain proteins does not explain how TNFR1 induces the tyrosine phosphorylation of intracellular proteins, which are important to cellular responses induced by TNFR1. In this study, we show that TNFR1 associates with Jak2, c-Src, and PI3K in various cell types. Jak2 and c-Src constitutively associate with and are constitutively active in the TNFR1 complex. Stimulation with TNF induces a time-dependent change in the level of Jak2, c-Src, and PI3K associated with TNFR1. The tyrosine kinase activity of the complex varies with the level of tyrosine kinase associated with TNFR1. TNFR1/c-Src plays a role in activating Akt, but not JNK or p38 MAPK, whereas TNFR1/Jak2 plays a role in activating p38 MAPK, JNK, and Akt. TNFR1/c-Src, but not TNFR1/Jak2, plays an obligate role in the activation of NF-κB by TNF, whereas TNFR1/Jak2, but not TNFR1/c-Src, plays an obligate role in the activation of STAT3. Activation of TNFR1 increased the expression of vascular endothelial growth factor, p21WAF1/CIP1, and manganese superoxide dismutase in MCF7 breast cancer cells, and increased the expression of CCl2/MCP-1 and IL-1β in THP-1 macrophages. Inhibitors of Jak2 and c-Src impaired the induction of each of these target proteins. These observations show that TNFR1 associates with and uses nonreceptor tyrosine kinases to engage signaling pathways, activate transcription factors, and modulate gene expression in cells.

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Section: Discussionsupporting

confidence: 76%

Type 1 TNF Receptor Forms a Complex with and Uses Jak2 and c-Src to Selectively Engage Signaling Pathways That Regulate Transcription Factor Activity

Pincheira

Castro

Özeş

et al. 2008

The Journal of Immunology

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“…The enhanced inflammatory response and leukocyte recruitment occurring after infection with highly pathogenic strains of influenza has been suggested to be dependent on TNF-and i-NOS-producing dendritic cells, as well as the CCR2 receptor (1,23). Epithelial CCL2 is rapidly induced in response to CD8 þ T-cell recognition in vitro and in vivo (32,43,45), and appears to require both TNF receptors, TNF-R1 and TNF-R2 (24).…”

mentioning

confidence: 99%

Interference with Intraepithelial TNF-α Signaling Inhibits CD8⁺T-Cell-Mediated Lung Injury in Influenza Infection

Srikiatkhachorn

Chintapalli

et al. 2010

Viral Immunology

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CD8þ T-cell-mediated pulmonary immunopathology in respiratory virus infection is mediated in large part by antigen-specific TNF-a expression by antiviral effector T cells, which results in epithelial chemokine expression and inflammatory infiltration of the lung. To further define the signaling events leading to lung epithelial chemokine production in response to CD8 þ T-cell antigen recognition, we expressed the adenoviral 14.7K protein, a putative inhibitor of TNF-a signaling, in the distal lung epithelium, and analyzed the functional consequences. Distal airway epithelial expression of 14.7K resulted in a significant reduction in lung injury resulting from severe influenza pneumonia. In vitro analysis demonstrated a significant reduction in the expression of an important mediator of injury, CCL2, in response to CD8 þ T-cell recognition, or to TNF-a. The inhibitory effect of 14.7K on CCL2 expression resulted from attenuation of NF-kB activity, which was independent of Ik-Ba degradation or nuclear translocation of the p65 subunit. Furthermore, epithelial 14.7K expression inhibited serine phosphorylation of Akt, GSK-3b, and the p65 subunit of NF-kB, as well as recruitment of NF-kB for DNA binding in vivo. These results provide insight into the mechanism of 14.7K inhibition of NF-kB activity, as well as further elucidate the mechanisms involved in the induction of T-cell-mediated immunopathology in respiratory virus infection.

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“…Thus, focus has shifted to CC chemokines, including monocyte chemotactic protein-1 (MCP-1), which have a role in the tissue recruitment of T cells. Pulmonary epithelial cells are capable of secreting MCP-1 in response to infectious stimulation, and epithelial MCP-1 mediates the pulmonary recruitment of CD8 ϩ T cells (42,62). In addition, a role for MCP-1/CC chemokine receptor 2 (MCP-1/CCR2) signaling in the repair of damaged pulmonary epithelium has been suggested (10).…”

mentioning

confidence: 99%

Pneumocystisstimulates MCP-1 production by alveolar epithelial cells through a JNK-dependent mechanism

Wang¹,

Gigliotti²,

Bhagwat³

et al. 2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Pneumocystis carinii is an opportunistic fungal pathogen that causes pneumonia (PCP) in immunocompromised individuals. Recent studies have demonstrated that the host's immune response is clearly responsible for the majority of the pathophysiological changes associated with PCP. P. carinii interacts closely with alveolar epithelial cells (AECs); however, the nature and pathological consequences of the epithelial response remain poorly defined. Monocyte chemotactic protein-1 (MCP-1) is involved in lung inflammation, immunity, and epithelial repair and is upregulated during PCP. To determine whether AECs are an important source of MCP-1 in the P. carinii-infected lung, in vivo and in vitro studies were performed. In situ hybridization showed that MCP-1 mRNA was localized to cells with morphological characteristics of AECs in the lungs of infected mice. In vitro studies demonstrated that P. carinii stimulated a time-and dose-dependent MCP-1 response in primary murine type II cells that was preceded by JNK activation. Pharmacological inhibition of JNK nearly abolished P. carinii-stimulated MCP-1 production, while ERK, p38 MAPK, and TNF receptor signaling were not required. Furthermore, delivery of a JNK inhibitory peptide specifically to pulmonary epithelial cells using a recombinant adenovirus vector blocked the early lung MCP-1 response following intratracheal instillation of infectious P. carinii. JNK inhibition did not affect P. carinii-stimulated production of macrophage inflammatory protein-2 in vitro or in vivo, indicating that multiple signaling pathways are activated in P. carinii-stimulated AECs. These data demonstrate that AECs respond to P. carinii in a proinflammatory manner that may contribute to the generation of immune-mediated lung injury. inflammation; epithelial; AIDS PNEUMONIA INDUCED by Pneumocystis carinii (PCP) continues to be the most common AIDS-defining illness as well as an important cause of morbidity and mortality in patients with a wide array of immunosuppressive conditions. Most recent studies indicate that, although the presence of P. carinii is obviously a factor in the development of lung injury, pulmonary inflammation is a major determinant of the severity of PCP (5,27,53,54). In AIDS patients with profound reductions in CD4 ϩ T cell numbers, bronchoalveolar lavage (BAL) fluid IL-8 and neutrophil concentrations, but not organism numbers, correlate with severity of PCP (5, 23, 28). In addition, clinical studies of immune-reconstituted PCP patients and controlled animal studies have both demonstrated that inflammatory mediators are released, and immune and inflammatory cells are recruited to the lung in response to P. carinii (2,25,38,39). More defined studies in mice have identified specific T cell subsets as having prominent roles in the lung injury associated with PCP (54, 57). For example, CD8 ϩ T cells are responsible for much of the PCP-associated lung injury that occurs in CD4-deficient hosts (17). Therefore, recent studies have focused on the mechanisms by which T cells accumu...

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Lung Epithelial NF-κB and Stat1 Signaling in Response to CD8⁺T Cell Antigen Recognition

Cited by 12 publications

References 43 publications

Type 1 TNF Receptor Forms a Complex with and Uses Jak2 and c-Src to Selectively Engage Signaling Pathways That Regulate Transcription Factor Activity

Type 1 TNF Receptor Forms a Complex with and Uses Jak2 and c-Src to Selectively Engage Signaling Pathways That Regulate Transcription Factor Activity

Interference with Intraepithelial TNF-α Signaling Inhibits CD8⁺T-Cell-Mediated Lung Injury in Influenza Infection

Pneumocystisstimulates MCP-1 production by alveolar epithelial cells through a JNK-dependent mechanism

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Lung Epithelial NF-κB and Stat1 Signaling in Response to CD8+T Cell Antigen Recognition

Cited by 12 publications

References 43 publications

Type 1 TNF Receptor Forms a Complex with and Uses Jak2 and c-Src to Selectively Engage Signaling Pathways That Regulate Transcription Factor Activity

Type 1 TNF Receptor Forms a Complex with and Uses Jak2 and c-Src to Selectively Engage Signaling Pathways That Regulate Transcription Factor Activity

Interference with Intraepithelial TNF-α Signaling Inhibits CD8+T-Cell-Mediated Lung Injury in Influenza Infection

Pneumocystisstimulates MCP-1 production by alveolar epithelial cells through a JNK-dependent mechanism

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Lung Epithelial NF-κB and Stat1 Signaling in Response to CD8⁺T Cell Antigen Recognition

Interference with Intraepithelial TNF-α Signaling Inhibits CD8⁺T-Cell-Mediated Lung Injury in Influenza Infection