Adrenal Steroids Modulate the Immune Response during Brucella abortus Infection by a Mechanism That Depends on the Regulation of Cytokine Production

Abstract

bHuman brucellosis is a protean disease with a diversity of clinical signs and symptoms resulting from infection with Brucella species. Recent reports suggest a cross-regulation between adrenal steroids (cortisol and dehydroepiandrosterone [DHEA]) and the immune system. Monocytes and macrophages are the main replication niche for Brucella. Therefore, we investigated the role of adrenal hormones on the modulation of the immune response mediated by macrophages in B. abortus infection. Cortisol treatment during B. abortus infection significantly inhibits cytokine, chemokine, and MMP-9 secretion. In contrast, DHEA treatment had no effect. However, DHEA treatment increases the expression of costimulatory molecules (CD40, CD86), the adhesion molecule CD54, and major histocompatibility complex class I (MHC- Human brucellosis is characterized by a great diversity of clinical manifestations resulting from infection with Brucella species (4). It is chiefly an inflammatory disease. Inflammation is present both in the acute and chronic phases of the disease and in practically all of the organs affected. Clinical signs of such inflammation are undulant fever, endocarditis, arthritis, osteomyelitis, meningitis, pleocytosis, cellular infiltration of the joints, orchitis, nephritis, hepatic granuloma, etc. (5).IBrucella abortus infection elicits a vigorous Th1 immune response, which also activates cytotoxic T lymphocytes (6-9). Despite the recognition that Th1 immunity is crucial for the control of Brucella infection, several aspects of the immune response, i.e., how the innate immune response shapes the adaptive Th1 immune response and why Th1 immunity is not sufficient to completely eradicate the infection, constitute a conundrum. Macrophages/monocytes were recognized to play an important role in resistance to facultative intracellular bacteria such as Brucella, and activation of macrophages by specifically committed T lymphocytes formed the basis for cell-mediated immunity. However, B. abortus is endowed with a panoply of survival stratagems to evade immune responses and survive inside macrophages, creating a safe niche of replication inside the host (10-13).Several cytokines that are produced during B. abortus infec- [18][19][20]. In previous studies, significantly higher levels of cortisol in serum were reported in patients with acute brucellosis than in brucellosis patients at the end of antibiotic treatment or than in healthy subjects (21). In addition, adrenal glands are enlarged in patients with acute brucellosis but return to normal size after therapy (21). Of note, Th1 Citation Gentilini MV, Velásquez LN, Barrionuevo P, Arriola Benitez PC, Giambartolomei GH, Delpino MV. 2015. Adrenal steroids modulate the immune response during Brucella abortus infection by a mechanism that depends on the regulation of cytokine production.

Inhibition of Osteoblast Function by Brucella abortus is Reversed by Dehydroepiandrosterone and Involves ERK1/2 and Estrogen Receptor

“…In this context, glucocorticoids and dehydroepiandrosterone (DHEA) may exert important influences on the establishment of the type of immune responses that humans develop against Brucella infection. Accordingly, in previous studies it has been demonstrated that cortisol levels were more elevated in patients with acute brucellosis than in healthy individuals ( 10 , 11 ). In addition, we have previously demonstrated that steroid hormones have a role in the modulation of macrophage response during B. abortus infection ( 11 ).…”

“…Accordingly, in previous studies it has been demonstrated that cortisol levels were more elevated in patients with acute brucellosis than in healthy individuals ( 10 , 11 ). In addition, we have previously demonstrated that steroid hormones have a role in the modulation of macrophage response during B. abortus infection ( 11 ). Brucella survives and replicate within vacuolar phagocytic compartments of macrophages ( 12 ).…”

Establishment of Chronic Infection: Brucella's Stealth Strategy

“…For clearance of Brucella , IFN-γ-mediated type I immune responses are essential (Goenka et al, 2011 ). Brucella modulates MHC-I and MHC-II expression prompted by IFN-γ, a mechanism that depends on cytokine regulation (Gentilini et al, 2015 ), which results in inhibition of MHC-I and MHC-II molecules (Barrionuevo et al, 2008 , 2013 ).…”

Estudo do potencial imunomodulador de Dehidroepiandrosterona (DHEA) na inflamação intestinal experimental

“…A administração de DHEA também melhora as respostas imunes contra uma grande variedade de agentes patogênicos virais letais, infecções bacterianas e parasitárias, nas quais o efeito benéfico deste hormônio tem sido atribuído às suas propriedades imunomoduladoras (Bongiovanni, Mata-Espinosa et al 2015, Gentilini, Velasquez et al 2015. Por exemplo, a terapia com DHEA mostrou ser eficaz contra a infecção experimental pelo Trypanosoma cruzi, promovendo aumento das concentrações de NO, IL-12, IL-2 e IFN-ɣ (Santos, Toldo et al 2008, Caetano, Santello et al 2009, Zeckey, Hildebrand et al 2010.…”

“…Como pode ser visto em diferentes estudos, o DHEA interfere no sistema imunológico de diversas formas, que variam de acordo com o modelo experimental, podendo, por exemplo, modular a função de células imunológicas através da regulação da produção de diferentes citocinas (Cheng andTseng 2000, Li, Tang et al 2014). Ainda, o tratamento com DHEA provou ser eficaz contra a infecção por diferentes agentes patogênicos como vírus, bactérias e parasitas (Santos, Toldo et al 2008, Caetano, Santello et al 2009, Zeckey, Hildebrand et al 2010, D'Attilio, Bozza et al 2012, Bongiovanni, Mata-Espinosa et al 2015, Gentilini, Velasquez et al 2015.…”