In patients with active brucellosis, the liver is frequently affected by histopathologic lesions, such as granulomas, inflammatory infiltrations, and parenchymal necrosis. Herein, we examine some potential mechanisms of liver damage in brucellosis. We demonstrate that Brucella abortus infection inhibits matrix metalloproteinase-9 (MMP-9) secretion and induces collagen deposition and tissue inhibitor of matrix metalloproteinase-1 secretion induced by hepatic stellate cells (LX-2). These phenomena depend on transforming growth factor-β1 induction. In contrast, supernatants from B. abortus-infected hepatocytes and monocytes induce MMP-9 secretion and inhibit collagen deposition in hepatic stellate cells. Yet, if LX-2 cells are infected with B. abortus, the capacity of supernatants from B. abortus-infected hepatocytes and monocytes to induce MMP-9 secretion and inhibit collagen deposition is abrogated. These results indicate that depending on the balance between interacting cells and cytokines of the surrounding milieu, the response of LX-2 cells could be turned into an inflammatory or fibrogenic phenotype. Livers from mice infected with B. abortus displayed a fibrogenic phenotype with patches of collagen deposition and transforming growth factor-β1 induction. This study provides potential mechanisms of liver immune response induced by B. abortus-infected hepatic stellate cells. In addition, these results demonstrate that the cross talk of these cells with hepatocytes and macrophages implements a series of interactions that may contribute to explaining some of mechanisms of liver damage observed in human brucellosis.

Arthritis is one of the most common complications of human active brucellosis, but its pathogenic mechanisms have not been completely elucidated. In this paper, we describe the role of synoviocytes in the pathogenesis of brucellar arthritis. Our results indicate that Brucella abortus infection inhibited synoviocyte apoptosis through the upregulation of antiapoptotic factors (cIAP-2, clusterin, livin, and P21/CIP/CDNK1A). In contrast, infection did not change the expression of proteins that have been involved in apoptosis induction such as Bad, Bax, cleaved procaspase 3, CytC, and TRAIL, among others; or their expression was reduced, as occurs in the case of P-p53(S15). In addition, B. abortus infection induced upregulation of adhesion molecules (CD54 and CD106), and the adhesion of monocytes and neutrophils to infected synoviocytes was significantly higher than to uninfected cells. Despite this increased adhesion, B. abortus-infected synoviocytes were able to inhibit apoptosis induced by supernatants from B. abortus-infected monocytes and neutrophils. Moreover, B. abortus infection increased soluble and membrane RANKL expression in synoviocytes that further induced monocytes to undergo osteoclastogenesis. The results presented here shed light on how the interactions of B. abortus with synovial fibroblasts may have an important role in the pathogenesis of brucellar arthritis.

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.