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1.
J Immunol ; 199(7): 2503-2514, 2017 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-28835457

RESUMO

Heterodimeric IL-27 (p28/EBV-induced gene 3) is an important member of the IL-6/IL-12 cytokine family. IL-27 is predominantly synthesized by mononuclear phagocytes and exerts immunoregulatory functional activities on lymphocytic and nonlymphocytic cells during infection, autoimmunity or neoplasms. There is a great body of evidence on the bidirectional interplay between the autonomic nervous system and immune responses during inflammatory disorders, but so far IL-27 has not been defined as a part of these multifaceted neuroendocrine networks. In this study, we describe the role of catecholamines (as mediators of the sympathetic nervous system) related to IL-27 production in primary mouse macrophages. Noradrenaline and adrenaline dose-dependently suppressed the release of IL-27p28 in LPS/TLR4-activated macrophages, which was independent of α1 adrenoceptors. Instead, ß2 adrenoceptor activation was responsible for mediating gene silencing of IL-27p28 and EBV-induced gene 3. The ß2 adrenoceptor agonists formoterol and salbutamol mediated suppression of IL-27p28 production, when triggered by zymosan/TLR2, LPS/TLR4, or R848/TLR7/8 activation, but selectively spared the polyinosinic-polycytidylic acid/TLR3 pathway. Mechanistically, ß2 adrenergic signaling reinforced an autocrine feedback loop of macrophage-derived IL-10 and this synergized with inhibition of the JNK pathway for limiting IL-27p28. The JNK inhibitors SP600125 and AEG3482 strongly decreased intracellular IL-27p28 in F4/80+CD11b+ macrophages. In endotoxic shock of C57BL/6J mice, pharmacologic activation of ß2 adrenoceptors improved the severity of shock, including hypothermia and decreased circulating IL-27p28. Conversely, IL-27p28 was 2.7-fold increased by removal of the catecholamine-producing adrenal glands prior to endotoxic shock. These data suggest a novel role of the sympathetic neuroendocrine system for the modulation of IL-27-dependent acute inflammation.


Assuntos
Epinefrina/farmacologia , Interleucinas/imunologia , Interleucinas/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Norepinefrina/farmacologia , Albuterol/farmacologia , Animais , Antracenos/farmacologia , Células Cultivadas , Fumarato de Formoterol/farmacologia , Inflamação , Interleucina-10/biossíntese , Interleucina-10/imunologia , Interleucinas/sangue , Interleucinas/genética , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Poli I-C/metabolismo , Receptores Adrenérgicos/efeitos dos fármacos , Choque Séptico , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Sistema Nervoso Simpático/imunologia , Sistema Nervoso Simpático/fisiologia , Tiadiazóis/farmacologia , Receptor 3 Toll-Like/metabolismo , Zimosan/farmacologia
2.
J Med Case Rep ; 14(1): 135, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859260

RESUMO

BACKGROUND: Rituximab is a well-established component of treatment regimens for B-cell non-Hodgkin lymphoma. Rituximab binds the CD20 antigen on the surface of B lymphocytes, causing an enhanced clearance of malignant and benign B cells. Thus, rituximab leads to depletion of normal B lymphocytes as well, which can cause substantial immunodeficiency. Ibrutinib inhibits the Bruton tyrosine kinase and thereby B-cell activity. It is used for the treatment of different B-lymphocyte malignancies, such as mantle cell lymphoma. Recently, the combination of both drugs has been tested in various clinical scenarios. CASE PRESENTATION: We present a case of disseminated enterovirus infection resulting from combined rituximab and ibrutinib maintenance treatment in a 57-year-old Caucasian patient. with mantle cell lymphoma. Initially presenting with myositis symptoms, further diagnostic investigation revealed myocarditis, enteritis, myeloencephalitis, and hepatitis. These organ manifestations led to potentially life-threatening complications such as rhabdomyolysis, delirium, and heart rhythm disturbances. After treatment with high-dose intravenous immunoglobulins, virus clearance was achieved and organ functions could be restored. CONCLUSIONS: This case emphasizes the risk of combined therapy with rituximab/ibrutinib for severe immune-related side effects with the necessity of continuous patient monitoring. High-dose intravenous therapy should be considered as treatment for severe enterovirus infection. In severe enterovirus infections, we recommend subtyping for the development of efficient preventive and therapeutic strategies.


Assuntos
Infecções por Enterovirus , Linfoma de Célula do Manto , Adenina/análogos & derivados , Adulto , Antígenos CD20 , Infecções por Enterovirus/tratamento farmacológico , Humanos , Linfoma de Célula do Manto/tratamento farmacológico , Pessoa de Meia-Idade , Piperidinas , Rituximab/efeitos adversos
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