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1.
J Infect Dis ; 217(11): 1821-1831, 2018 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-29438524

RESUMO

Cyclic adenosine monophosphate (cAMP) is critical in immune regulation, and its role in tuberculosis infection remains unclear. We determined the levels of cAMP in peripheral blood mononuclear cells (PBMC) from tuberculosis patients and the mechanisms for cAMP suppression of IFN-γ production. PBMC from tuberculosis patients contained significantly elevated cAMP than latent tuberculosis infected subjects (LTBI), with an inverse correlation with IFN-γ production. Consistent with this, the expression of cAMP response element binding protein (CREB), activating transcription factor (ATF)-2 and c-Jun were reduced in tuberculosis patients compared with LTBI. PKA type I specific cAMP analogs inhibited Mtb-stimulated IFN-g production by PBMC through suppression of Mtb-induced IFN-γ promoter binding activities of CREB, ATF-2, and c-Jun and also miR155, the target miRNA of these transcription factors. Neutralizing both IL-10 and TGF-ß1 or supplementation of IL-12 restored cAMP-suppressed IFN-g production. We conclude that increased cAMP inhibits IFN-g production through PKA type I pathway in tuberculosis infection.


Assuntos
Proteína Quinase Tipo I Dependente de AMP Cíclico/imunologia , AMP Cíclico/imunologia , Interferon gama/imunologia , Tuberculose Latente/imunologia , Mycobacterium tuberculosis/imunologia , Linfócitos T/imunologia , Fator 2 Ativador da Transcrição/imunologia , Antígenos de Bactérias/imunologia , Humanos , Interleucina-10/imunologia , Leucócitos Mononucleares/imunologia , Regiões Promotoras Genéticas/imunologia , Ligação Proteica/imunologia , Transdução de Sinais/imunologia
2.
Med Hypotheses ; 86: 56-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26804598

RESUMO

Despite the tremendous progress in last few years, the cancer immunotherapy has not yet improved disease-free because of the tumor-associated immune suppression being a major barrier. Novel trends to enhance cancer immunotherapy aims at harnessing the therapeutic manipulation of signaling pathways mediating the tumor-associated immune suppression, with the general aims of: (a) reversing the tumor immune suppression; (b) enhancing the innate and adaptive components of anti-tumor immunosurveillance, and (c) protecting immune cells from the suppressive effects of T regulatory cells (Tregs) and the tumor-derived immunoinhibitory mediators. A particular striking example in this context is the cyclic adenosine monophosphate (cAMP)-dependent protein kinase A type I (PKAI) pathway. Oncogenic cAMP/PKAI signaling has long been implicated in the initiation and progression of several human cancers. Emerging data indicate that cAMP/PKAI signaling also contributes to tumor- and Tregs-derived suppression of innate and adaptive arms of anti-tumor immunosurveillance. Therapeutically, selective PKAI inhibitors have been developed which have shown promising anti-cancer activity in pre-clinical and clinical settings. Rp-8-Br-cAMPS is a selective PKAI antagonist that is widely used as a biochemical tool in signal transduction research. Collateral data indicate that Rp-8-Br-cAMPS has shown immune-rescuing potential in terms of enhancing the innate and adaptive anti-tumor immunity, as well as protecting adaptive T cells from the suppressive effects of Tregs. Therefore, this proposal specifically implicates that combining selective PKAI antagonists/inhibitors with cancer immunotherapy may have multifaceted benefits, such as rescuing the endogenous anti-tumor immunity, enhancing the efficacy of cancer immunotherapy, and direct anti-cancer effects.


Assuntos
Proteína Quinase Tipo I Dependente de AMP Cíclico/antagonistas & inibidores , Proteína Quinase Tipo I Dependente de AMP Cíclico/imunologia , Imunoterapia/métodos , Neoplasias/enzimologia , Neoplasias/terapia , Inibidores de Proteínas Quinases/administração & dosagem , Antineoplásicos/administração & dosagem , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Modelos Imunológicos , Terapia de Alvo Molecular/métodos , Neoplasias/imunologia , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
3.
Sci Signal ; 5(210): ra12, 2012 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-22317922

RESUMO

Macrophage ingestion of the yeast Candida albicans requires its recognition by multiple receptors and the activation of diverse signaling programs. Synthesis of the lipid mediator prostaglandin E(2) (PGE(2)) and generation of cyclic adenosine monophosphate (cAMP) also accompany this process. Here, we characterized the mechanisms underlying PGE(2)-mediated inhibition of phagocytosis and filamentous actin (F-actin) polymerization in response to ingestion of C. albicans by alveolar macrophages. PGE(2) suppressed phagocytosis and F-actin formation through the PGE(2) receptors EP2 and EP4, cAMP, and activation of types I and II protein kinase A. Dephosphorylation and activation of the actin depolymerizing factor cofilin-1 were necessary for these inhibitory effects of PGE(2). PGE(2)-dependent activation of cofilin-1 was mediated by the protein phosphatase activity of PTEN (phosphatase and tensin homolog deleted on chromosome 10), with which it directly associated. Because enhanced production of PGE(2) accompanies many immunosuppressed states, the PTEN-dependent pathway described here may contribute to impaired antifungal defenses.


Assuntos
Candida albicans/imunologia , Candidíase/imunologia , Cofilina 1/imunologia , Dinoprostona/imunologia , Tolerância Imunológica , Macrófagos Alveolares/imunologia , PTEN Fosfo-Hidrolase/imunologia , Fagocitose/imunologia , Actinas/imunologia , Actinas/metabolismo , Animais , Candida albicans/metabolismo , Candidíase/metabolismo , Células Cultivadas , Cofilina 1/metabolismo , AMP Cíclico/imunologia , AMP Cíclico/metabolismo , Proteína Quinase Tipo I Dependente de AMP Cíclico/imunologia , Proteína Quinase Tipo I Dependente de AMP Cíclico/metabolismo , Proteína Quinase Tipo II Dependente de AMP Cíclico/imunologia , Proteína Quinase Tipo II Dependente de AMP Cíclico/metabolismo , Dinoprostona/biossíntese , Feminino , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/microbiologia , PTEN Fosfo-Hidrolase/metabolismo , Fosforilação/imunologia , Ratos , Ratos Wistar , Receptores de Prostaglandina E Subtipo EP2/imunologia , Receptores de Prostaglandina E Subtipo EP2/metabolismo , Receptores de Prostaglandina E Subtipo EP4/imunologia , Receptores de Prostaglandina E Subtipo EP4/metabolismo
4.
Scand J Immunol ; 74(6): 568-73, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21854406

RESUMO

The distal pole complex (DPC) assembles signalling proteins at the T cell pole opposite the immunological synapse (IS) and is thought to facilitate T cell activation by sequestering negative regulatory molecules away from the T cell receptor-proximal signalling machinery. Here, we report the translocation of type I protein kinase A (PKA) to the DPC in a fraction of T cells following activation and the localization of type I PKA with known components of the DPC. We propose that sequestration of type I PKA and concomitant loss of cAMP-mediated negative regulation at the IS may be necessary to allow full T cell activation. Moreover, composition of the DPC appears to be modulated by type I PKA activity, as the antagonist Rp-8-Br-cAMPS inhibited translocation of type I PKA and other DPC proteins.


Assuntos
Proteína Quinase Tipo I Dependente de AMP Cíclico/imunologia , Linfócitos T/imunologia , Movimento Celular , Células Cultivadas , Proteína Quinase Tipo I Dependente de AMP Cíclico/metabolismo , Humanos , Ativação Linfocitária , Ligação Proteica , Linfócitos T/citologia , Linfócitos T/enzimologia
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