Bacterium-dependent induction of cytokines in mononuclear cells and their pathologic consequences in vivo.
(25/6604)
Viridans streptococci are a heterogeneous group of gram-positive bacteria that are normal inhabitants of the mouth. These organisms are thought to contribute significantly to the etiology of infective endocarditis, although recently they have been implicated in serious infections in other settings. Another group of oral bacteria, gram-negative anaerobes, is associated with chronic dental infections, such as periodontal diseases or endodontic lesion formation. We evaluated the ability of the oral pathogens Streptococcus mutans and Porphyromonas endodontalis to induce a pathogenic response in vivo, with the goal of quantifying the inflammatory response in soft tissue by measuring leukocyte recruitment and hard tissues by measuring osteoclastogenesis. S. mutans induced a strong inflammatory response and was a potent inducer of osteoclast formation, while P. endodontalis was not. To further study the mechanisms by which P. endodontalis and S. mutans elicit significantly different levels of inflammatory responses in vivo, we tested the capacity of each to induce production of cytokines by mononuclear cells in vitro. S. mutans stimulated high levels of interleukin-12 (IL-12), gamma interferon (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha), all of which are associated with inflammation, enhanced monocyte function, and generation of a Th1 response. In contrast, P. endodontalis stimulated production of IL-10 but not of TNF-alpha, IL-12, or IFN-gamma. These results demonstrate that oral pathogens differ dramatically in their abilities to induce inflammatory and immunoregulatory cytokines. Moreover, there is a high degree of correlation between the cytokine profile induced by these bacteria in vitro and their pathogenic capacity in vivo. (+info)
Autoregulatory effect of interleukin-10 on proinflammatory cytokine production by Porphyromonas gingivalis lipopolysaccharide-tolerant human monocytes.
(26/6604)
Pretreatment of human peripheral blood monocytes with a very low concentration (0.1 ng/ml) of Porphyromonas gingivalis lipopolysaccharides (LPS) resulted in a significant decrease of interleukin-6 (IL-6) production, but not IL-8 production, by restimulation of a high concentration (1 microg/ml) of the same LPS. In contrast, the same pretreatment with Escherichia coli LPS resulted in the enhanced production of both IL-6 and IL-8 after restimulation. The selective induction by P. gingivalis LPS tolerance of IL-6 production developed in a time-dependent manner during the primary culture. P. gingivalis LPS-pretreated cells were also refractory to a high-dose E. coli LPS restimulation in terms of IL-6 production. The expression of IL-6 mRNA decreased 10 h after restimulation of P. gingivalis LPS-pretreated monocytes. Furthermore, an up-regulation of anti-inflammatory cytokine IL-10 upon a second high-dose LPS rechallenge occurred at the same time point in the pretreated cells. We studied the role of IL-10 in the process of IL-6 down-regulation. Neutralization by an anti-IL-10 polyclonal antibody prevented IL-6 down-regulation in P. gingivalis LPS-pretreated monocytes, whereas IL-8 production was not affected. Addition of exogenous IL-10 during the high-dose LPS stimulation of untreated cells substituted for the LPS pretreatment and resulted in the inhibition of IL-6 production in a dose-dependent manner. A higher dose of IL-10 was required to suppress IL-8 synthesis from monocytes. Our data suggest that IL-10 mediates IL-6 down-regulation in P. gingivalis LPS-tolerant monocytes in an autocrine manner. (+info)
Regulation of inflammatory responses by oncostatin M.
(27/6604)
Oncostatin M (OM) is a pleiotropic cytokine produced late in the activation cycle of T cells and macrophages. In vitro it shares properties with related proteins of the IL-6 family of cytokines; however, its in vivo properties and physiological function are as yet ill defined. We show that administration of OM inhibited bacterial LPS-induced production of TNF-alpha and lethality in a dose-dependent manner. Consistent with these findings, OM potently suppressed inflammation and tissue destruction in murine models of rheumatoid arthritis and multiple sclerosis. T cell function and Ab production were not impaired by OM treatment. Taken together these data indicate the activities of this cytokine in vivo are antiinflammatory without concordant immunosuppression. (+info)
Bacterial peptidoglycan polysaccharides in sterile human spleen induce proinflammatory cytokine production by human blood cells.
(28/6604)
Peptidoglycan (PG) is the major component of the cell wall of gram-positive bacteria. In vitro, PG isolated from conventional bacterial cultures can induce secretion of proinflammatory cytokines by human monocytes, indicating that PG may be involved in immune responses against infections by gram-positive bacteria. To investigate the biologic activity of PG in human tissues, an improved method was developed to isolate significant amounts of PG from sterile human spleen tissue. Biochemical analysis demonstrated that PG isolated from human spleen is largely intact. Human whole blood cell cultures were able to produce the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1 and -6 after stimulation with PG isolated from human spleen. Cytokine induction was not sensitive to inhibition by polymyxin B, in contrast to lipopolysaccharide. Collectively, the data show that intact PG in sterile human tissue is biologically active and may induce local proinflammatory cytokine production. (+info)
Rifampin reduces early mortality in experimental Streptococcus pneumoniae meningitis.
(29/6604)
Compared with beta-lactam antibiotics, rifampin releases smaller quantities of proinflammatory cell wall products from Streptococcus pneumoniae in vitro. Mice infected intracerebrally with S. pneumoniae were treated subcutaneously with 2-mg doses of rifampin or ceftriaxone (n=43 each) every 12 h for 3 days and then observed for another 3 days. Rifampin reduced overall mortality from 49% to 26% (P=.04). Kaplan-Meyer analysis revealed a substantial reduction of mortality during the first 24 h in mice receiving rifampin (difference in survival time: P=.007). Eight h after receiving a single 2-mg dose of rifampin or ceftriaxone, rifampin-treated mice had lower serum and cerebrospinal fluid concentrations of lipoteichoic and teichoic acids than did ceftriaxone-treated mice (median serum level: <0.5 vs. 27.0 ng/mL, P=.02; median cerebrospinal fluid level of pooled specimens: 97.5 vs. 206.0 ng/mL). Thus, the use of rifampin appears promising for reducing the release of proinflammatory bacterial components and decreasing early mortality in bacterial meningitis. (+info)
Differential induction of adhesion molecule and chemokine expression by LTalpha3 and LTalphabeta in inflammation elucidates potential mechanisms of mesenteric and peripheral lymph node development.
(30/6604)
Lymphotoxin (LT) is a member of the proinflammatory TNF family of cytokines that plays a critical role in the development of lymphoid tissue. It has previously been reported that the presence of the LTalpha transgene under the control of the rat insulin promoter results in inflammation at the sites of transgene expression. LTalpha transgene expression results in expression of the adhesion molecules VCAM, ICAM, peripheral node addressin (a marker of peripheral lymph nodes), and mucosal addressin cellular adhesion molecule (a marker of mucosal lymphoid tissue, including mesenteric lymph nodes). In this study to determine the mechanisms by which LT promotes inflammation and lymphoid tissue organization, we analyzed the regulation of expression of adhesion molecules and chemokines in LT transgenic mice. The results demonstrate that LTalpha3 induces expression of the adhesion molecules VCAM, ICAM, and mucosal addressin cellular adhesion molecule as well as the chemokines RANTES, IFN-inducible protein-10, and monocyte chemotactic protein-1, while LTalphabeta is required for the induction of peripheral node addressin that may contribute to the recruitment of L-selectinhigh CD44low naive T cells. These data provide candidate mediators of LT-induced inflammation as well as potential mechanisms by which LTalpha and LTalphabeta may differentially promote the development of mesenteric and peripheral lymph nodes. (+info)
Inflammatory cytokines and HIV-1-associated neurodegeneration: oncostatin-M produced by mononuclear cells from HIV-1-infected individuals induces apoptosis of primary neurons.
(31/6604)
Neurologic abnormalities are common in HIV-1-infected patients and often represent the dominant clinical manifestation of pediatric AIDS. The neurological dysfunction has been directly related to CNS invasion by HIV-1 that is principally, if not exclusively, supported by blood-derived monocytes/macrophages and lymphocytes. By using primary long term cultures of human fetal sensory neurons as well as sympathetic precursors-like neuronal cells, we determined that blood-derived mononuclear cells from HIV-1-infected individuals spontaneously release soluble mediators that can potently inhibit the growth and survival of developing neurons as well as the viability of postmitotic neuronal cells by inducing apoptotic cell death. Analysis of the cytokines produced by lymphomonocytic cells, HIV-1 infected or activated, indicated that oncostatin M (oncM) is a major mediator of these effects. Since low TGF-beta1 concentrations were capable of enhancing oncM-mediated neuronal alterations, our data indicate that by acting in concert with other cytokines, oncM may induce neuronal demise in both the developing and the mature brain. Thus, this cytokine may contribute to the setting of the neuronal cell damage observed in HIV-1-infected individuals. (+info)
Diagnosing occupational asthma: use of induced sputum.
(32/6604)
The diagnosis of occupational asthma (OA) needs to be made with as much objective evidence as possible. If there is airway inflammation, measurement of this should be an asset. The objective of this study was to investigate whether there is an increase in induced sputum and blood eosinophils and eosinophil cationic protein (ECP) in OA after work exposure. Patients were assessed after a 2-4 week period at work and away from work with cell counts and ECP assays performed blind to the clinical data. They were considered to have OA if symptoms were worse at work and there was a fall in forced expiratory volume in one second (FEV1) > or =20% or in the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) of four-fold or more compared with away from work. Patients whose symptoms were worse at work but had a change in FEV1 of <20% and in methacholine PC20 of less than four-fold were considered as controls. Sixteen patients were studied. Ten had OA and six were controls. Patients with OA had a significant increase in median (interquartile range) sputum eosinophils and ECP when at work compared with the periods out of work, 10.0 (17.05) versus 0.8 (1.6)% (p=0.007) and 3,840 (6,076) versus 116 (180) microg x L(-1) (p=0.01). They also had a higher blood eosinophil count, 0.3 (0.5) x 10(9) versus 0.2 (0.1) x 10(9) x L(-1) (p=0.013), and a trend towards higher serum ECP levels, 44.0 (20.0) versus 32.0 (18.5) microg x L(-1) (p=0.07). In conclusion, the proportion of eosinophils and levels of eosinophil cationic protein in sputum are particularly high at work in patients with occupational asthma, suggesting that the measurement of these factors can supplement other physiological outcomes in establishing the diagnosis of occupational asthma. (+info)