The underlying mechanisms of this phenomenon are currently unclear. independent of bacterial viability and was recapitulated by L-Omp19, a lipoprotein model, but not its LPS. and L-Omp19 readily activated p38 and Erk1/2 MAPK, thus enlisting these pathways among the kinase pathways that the bacteria may address as they invade astrocytes. Inhibition of p38 Abacavir or Erk1/2 significantly diminished MMP-9 secretion, and totally abrogated production of this MMP when both MAPK pathways were inhibited simultaneously. A concomitant abrogation of or L-Omp19 was completely abrogated when experiments were conducted in the presence of a TNF- neutralizing antibody. MMP-9 activity was detected in cerebrospinal fluid (CSF) samples from patients suffering from neurobrucellosis. Conclusions Our results indicate that the inflammatory response elicited by in astrocytes would lead to the production of MMP-9 and that MAPK may play a role in this phenomenon. MAPK inhibition may thus be considered as a strategy to control inflammation and CNS damage in neurobrucellosis. species . It is chiefly an inflammatory disease. Inflammation is present both in the acute and chronic phases of the disease and in virtually all of the organs affected. Clinical signs of such inflammation are undulant fever, endocarditis, arthritis, Abacavir osteomyelitis, meningitis, pleocytosis, cellular infiltration of the joints, orchitis, nephritis, hepatic granuloma, etc . In the central nervous system (CNS), where the function of neurons is normally protected by the maintenance of an antiinflammatory environment , infection with leads to an inflammatory disorder called neurobrucellosis which involves tissue destruction [4,5]. The underlying mechanisms of this phenomenon are currently unclear. Yet, a better understanding of the pathogenesis of neurobrucellosis would help if improvements are to be made on therapies that help to cure or ameliorate this form of the disease . Matrix metalloproteinases (MMP) are a family of calcium- and zinc-dependent proteinases that have been implicated in inflammatory tissue destruction in a range of Rabbit polyclonal to KIAA0317 pathological situations in the CNS, including experimental autoimmune encephalomyelitis, multiple sclerosis, and CNS tuberculosis [7-10]. Particularly, MMP-9 can degrade many structural components of the Abacavir blood-brain barrier and CNS tissue matrix, including type IV collagen, laminins, and fibronectin [11,12]. MMP-9 can also mediate direct damage to neurons  and MMP-9 knockout mice are protected against ischemic and post-traumatic damage which follows blood-brain barrier disruption . In addition, MMP have been implicated in tissue-destructive pathology in osteoarticular brucellosis [15-18]. Astrocytes are the most numerous cell type within the CNS, outnumbering neurons by a factor of ten. They are integral to both maintenance of the CNS tissue matrix and innate immunity within the CNS , and also the well-being of the blood-brain barrier [20,21]. In normal physiology MMP-9 secretion is highly regulated, and under these conditions astrocyte-derived MMP-9 participates in tissue remodeling and neurite extension [22,23]. Yet, astrocyte-derived MMP-9 may contribute to the development of a tissue-destructive phenotype in the CNS. Increased MMP-9 secretion is induced by pro-inflammatory Abacavir cytokines in a range of CNS diseases characterized by tissue-destructive pathology . We have recently demonstrated that upon infection with and regulates MAPK-dependent astrocyte MMP-9 secretion . In this study, Abacavir we investigated the cytokine network that regulates MMP secretion from S2308, H38 and 1330 were grown overnight in 10 ml of tryptic soy broth (TSB) with constant agitation at 37C. Bacteria were harvested by centrifugation for 15 minutes at 6,000 at 4C and washed twice in 10 ml of phosphate-buffered saline (PBS). Bacterial numbers in the cultures were estimated by comparing the optical densities at 600 nm with a standard curve obtained in our laboratory. To prepare inocula, cultures were diluted in sterile PBS to the desired bacterial concentration on the basis of the optical density readings, but the precise concentrations of inocula were determined by plating cells onto tryptic soy agar. To obtain.