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2.
Am J Respir Cell Mol Biol ; 66(1): 23-37, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34236953

RESUMEN

The U.S. Food and Drug Administration-approved proteasomal inhibitor bortezomib (BTZ) has attracted interest for its potential antifibrotic actions. However, neither its in vivo efficacy in lung fibrosis nor its dependence on proteasome inhibition has been conclusively defined. In this study, we assessed the therapeutic efficacy of BTZ in a mouse model of pulmonary fibrosis, developed an in vitro protocol to define its actions on diverse fibroblast activation parameters, determined its reliance on proteasome inhibition for these actions in vivo and in vitro, and explored alternative mechanisms of action. The therapeutic administration of BTZ diminished the severity of pulmonary fibrosis without reducing proteasome activity in the lung. In experiments designed to mimic this lack of proteasome inhibition in vitro, BTZ reduced fibroblast proliferation, differentiation into myofibroblasts, and collagen synthesis. It promoted dedifferentiation of myofibroblasts and overcame their characteristic resistance to apoptosis. Mechanistically, BTZ inhibited kinases important for fibroblast activation while inducing the expression of DUSP1 (dual-specificity protein phosphatase 1), and knockdown of DUSP1 abolished its antifibrotic actions in fibroblasts. Collectively, these findings suggest that BTZ exhibits a multidimensional profile of robust inhibitory actions on lung fibroblasts as well as antifibrotic actions in vivo. Unexpectedly, these actions appear to be independent of proteasome inhibition, instead attributable to the induction of DUSP1.


Asunto(s)
Bortezomib/uso terapéutico , Fibroblastos/patología , Inhibidores de Proteasoma/farmacología , Fibrosis Pulmonar/tratamiento farmacológico , Fibrosis Pulmonar/patología , Adulto , Apoptosis/efectos de los fármacos , Bleomicina , Bortezomib/farmacología , Desdiferenciación Celular/efectos de los fármacos , Línea Celular , Proliferación Celular/efectos de los fármacos , Fosfatasa 1 de Especificidad Dual/metabolismo , Factor 2 de Crecimiento de Fibroblastos/farmacología , Fibroblastos/efectos de los fármacos , Humanos , Miofibroblastos/efectos de los fármacos , Miofibroblastos/patología , FN-kappa B/metabolismo , Prostaglandinas/metabolismo , Transducción de Señal/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo , Receptor fas/metabolismo
3.
J Immunol ; 202(9): 2700-2709, 2019 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-30867240

RESUMEN

GM-CSF is required for alveolar macrophage (AM) development shortly after birth and for maintenance of AM functions throughout life, whereas M-CSF is broadly important for macrophage differentiation and self-renewal. However, the comparative actions of GM-CSF and M-CSF on AMs are incompletely understood. Interstitial macrophages (IMs) constitute a second major pulmonary macrophage population. However, unlike AMs, IM responses to CSFs are largely unknown. Proliferation, phenotypic identity, and M1/M2 polarization are important attributes of all macrophage populations, and in this study, we compared their modulation by GM-CSF and M-CSF in murine primary AMs and IMs. CSFs increased the proliferation capacity and upregulated antiapoptotic gene expression in AMs but not IMs. GM-CSF, but not M-CSF, reinforced the cellular identity, as identified by surface markers, of both cell types. GM-CSF, but not M-CSF, increased the expression of both M1 and M2 markers exclusively in AMs. Finally, CSFs enhanced the IFN-γ- and IL-4-induced polarization ability of AMs but not IMs. These first (to our knowledge) data comparing effects on the two pulmonary macrophage populations demonstrate that the activating actions of GM-CSF and M-CSF on primary AMs are not conserved in primary IMs.


Asunto(s)
Proliferación Celular/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Interferón gamma/inmunología , Interleucina-4/inmunología , Factor Estimulante de Colonias de Macrófagos/farmacología , Macrófagos Alveolares/inmunología , Animales , Antígenos de Diferenciación/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Factor Estimulante de Colonias de Macrófagos/inmunología , Macrófagos Alveolares/citología , Masculino , Ratones
4.
J Immunol ; 196(12): 5112-20, 2016 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-27183597

RESUMEN

Preservation of gas exchange mandates that the pulmonary alveolar surface restrain unnecessarily harmful inflammatory responses to the many challenges to which it is exposed. These responses reflect the cross-talk between alveolar epithelial cells (AECs) and resident alveolar macrophages (AMs). We recently determined that AMs can secrete suppressor of cytokine signaling (SOCS) proteins within microparticles. Uptake of these SOCS-containing vesicles by epithelial cells inhibits cytokine-induced STAT activation. However, the ability of epithelial cells to direct AM release of SOCS-containing vesicles in response to inflammatory insults has not been studied. In this study, we report that SOCS3 protein was elevated in bronchoalveolar lavage fluid of both virus- and bacteria-infected mice, as well as in an in vivo LPS model of acute inflammation. In vitro studies revealed that AEC-conditioned medium (AEC-CM) enhanced AM SOCS3 secretion above basal levels. Increased amounts of PGE2 were present in AEC-CM after LPS challenge, and both pharmacologic inhibition of PGE2 synthesis in AECs and neutralization of PGE2 in AEC-CM implicated this prostanoid as the major AEC-derived factor mediating enhanced AM SOCS3 secretion. Moreover, pharmacologic blockade of PGE2 synthesis or genetic deletion of a PGE2 synthase similarly attenuated the increase in bronchoalveolar lavage fluid SOCS3 noted in lungs of mice challenged with LPS in vivo. These results demonstrate a novel tunable form of cross-talk in which AECs use PGE2 as a signal to request SOCS3 from AMs to dampen their endogenous inflammatory responses during infection.


Asunto(s)
Células Epiteliales Alveolares/metabolismo , Líquido del Lavado Bronquioalveolar/inmunología , Dinoprostona/metabolismo , Inmunidad Innata , Macrófagos Alveolares/inmunología , Proteína 3 Supresora de la Señalización de Citocinas/metabolismo , Células Epiteliales Alveolares/inmunología , Animales , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/microbiología , Líquido del Lavado Bronquioalveolar/virología , Línea Celular Tumoral , Células Cultivadas , Medios de Cultivo , Inflamación , Lipopolisacáridos/inmunología , Macrófagos Alveolares/metabolismo , Ratones , Prostaglandina-E Sintasas/deficiencia , Prostaglandina-E Sintasas/genética , Ratas , Factor de Transcripción STAT3/inmunología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal , Proteína 3 Supresora de la Señalización de Citocinas/inmunología
5.
J Exp Med ; 212(5): 729-42, 2015 May 04.
Artículo en Inglés | MEDLINE | ID: mdl-25847945

RESUMEN

JAK-STAT signaling mediates the actions of numerous cytokines and growth factors, and its endogenous brake is the family of SOCS proteins. Consistent with their intracellular roles, SOCS proteins have never been identified in the extracellular space. Here we report that alveolar macrophages can secrete SOCS1 and -3 in exosomes and microparticles, respectively, for uptake by alveolar epithelial cells and subsequent inhibition of STAT activation. Secretion is tunable and occurs both in vitro and in vivo. SOCS secretion into lung lining fluid was diminished by cigarette smoking in humans and mice. Secretion and transcellular delivery of vesicular SOCS proteins thus represent a new model for the control of inflammatory signaling, which is subject to dysregulation during states of inflammation.


Asunto(s)
Micropartículas Derivadas de Células/inmunología , Células Epiteliales/inmunología , Macrófagos/inmunología , Alveolos Pulmonares/inmunología , Transducción de Señal/inmunología , Proteínas Supresoras de la Señalización de Citocinas/inmunología , Animales , Línea Celular Transformada , Micropartículas Derivadas de Células/patología , Células Epiteliales/patología , Femenino , Humanos , Inflamación/inmunología , Inflamación/patología , Quinasas Janus/inmunología , Masculino , Ratones , Alveolos Pulmonares/patología , Ratas , Ratas Wistar , Factores de Transcripción STAT/inmunología
6.
J Immunol ; 177(7): 4636-43, 2006 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-16982902

RESUMEN

Leishmania donovani, a protozoan parasite, inflicts a fatal disease, visceral leishmaniasis. The suppression of antileishmanial T cell responses that characterizes the disease was proposed to be due to deficiency of a T cell growth factor, IL-2. We demonstrate that during the first week after L. donovani infection, IL-2 induces IL-10 that suppresses the host-protective functions of T cells 14 days after infection. The observed suppression is concurrent with increased CD4+ glucocorticoid-induced TNF receptor+ T cells and Foxp3 expression in BALB/c mice, implicating IL-2-dependent regulatory T cell control of antileishmanial immune responses. Indeed, IL-2 and IL-10 neutralization at different time points after the infection demonstrates their distinct roles at the priming and effector phases, respectively, and establishes kinetic modulation of ongoing immune responses as a principle of a rational, phase-specific immunotherapy.


Asunto(s)
Inmunoterapia , Interleucina-10/biosíntesis , Interleucina-2/metabolismo , Leishmaniasis Visceral/inmunología , Linfocitos T/inmunología , Animales , Antígenos CD4/metabolismo , Relación Dosis-Respuesta a Droga , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Factores de Transcripción Forkhead/metabolismo , Interleucina-2/administración & dosificación , Leishmania donovani/inmunología , Ratones , Ratones Endogámicos BALB C , Receptores de Interleucina-2/metabolismo , Receptores del Factor de Necrosis Tumoral/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo
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