transforming-growth-factor-beta and Bacteremia

To characterize changes in serum cytokine levels in human immunodeficiency virus type 1 (HIV-1)-infected persons with Mycobacterium avium complex (MAC) bacteremia, the levels of IL-1alpha (interleukin-1alpha), IL-6, IL-10, tumor necrosis factor alpha (TNF-alpha), soluble type II TNF receptor (sTNF-RII), and transforming growth factor beta (TGF-beta) in serum were measured in two cohorts of HIV-1-infected persons with MAC bacteremia. The first cohort was part of a MAC prophylaxis study. Patients with bacteremia were matched with controls without bacteremia. Elevated IL-6, IL-10, TNF-alpha, sTNF-RII, and TGF-beta levels were noted at baseline for all subjects, a result consistent with advanced HIV-1 disease. IL-1alpha was not detected. No differences in cytokine levels in serum were noted at baseline and at the time of bacteremia between patients with MAC and controls. In the second cohort, subjects had serum samples collected at the time of MAC bacteremia and thereafter while on macrolide therapy. Serum samples at time of bacteremia were collected from HIV-1-infected persons at a time when neither highly active antiretroviral therapy (HAART) nor MAC prophylaxis was used routinely. MAC treatment resulted in decreased levels of IL-6 and TNF-alpha in serum, which were evident for IL-6 by 4 to 6 weeks and for TNF-alpha by 8 to 16 weeks. Thus, antibiotic treatment for MAC results in decreased levels of IL-6 and TNF-alpha in serum in HIV-1-infected persons who are not on HAART.

Topics: AIDS-Related Opportunistic Infections; Anti-Bacterial Agents; Anti-HIV Agents; Antigens, CD; Bacteremia; Case-Control Studies; Cohort Studies; Cytokines; Drug Therapy, Combination; HIV Infections; Humans; Interleukin-10; Interleukin-6; Macrolides; Mycobacterium avium Complex; Mycobacterium avium-intracellulare Infection; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type II; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Information on cytokine profiles in fungal sepsis (FS), an important cause of mortality in extremely low birthweight (ELBW) infants, is lacking. We hypothesized that cytokine profiles in the first 21 d of life in ELBW infants with FS differ from those with bacterial sepsis (BS) or no sepsis (NS).. In a secondary analysis of the National Institute of Child Health and Human Development Cytokine study, three groups were defined-FS (≥1 episode of FS), BS (≥1 episode of BS without FS), and NS. Association between 11 cytokines assayed in dried blood spots obtained on days 0-1, 3 ± 1, 7 ± 2, 14 ± 3, and 21 ± 3 and sepsis group was explored.. Of 1,066 infants, 89 had FS and 368 had BS. As compared with BS, FS was more likely to be associated with lower birthweight, vaginal delivery, patent ductus arteriosus, postnatal steroids, multiple central lines, longer respiratory support and hospital stay, and higher mortality (P < 0.05). Analyses controlling for covariates showed significant group differences over time for interferon-γ (IFN-γ), interleukin (IL)-10, IL-18, transforming growth factor-β (TGF-β), and tumor necrosis factor-α (TNF-α) (P < 0.05).. Significant differences in profiles for IFN-γ, IL-10, IL-18, TGF-β, and TNF-α in FS, BS, or NS in this hypothesis-generating secondary study require validation in rigorously designed prospective studies and may have implications for diagnosis and treatment.

Topics: Area Under Curve; Bacteremia; Case-Control Studies; Cytokines; Dried Blood Spot Testing; Fungemia; Humans; Infant, Extremely Low Birth Weight; Infant, Newborn; Infant, Premature; Interferon-gamma; Interleukin-10; Interleukin-18; Models, Statistical; ROC Curve; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Infection and bacteremia are common in sickle cell disease. We hypothesized that, consistent with evidence for the genetic modulation of other disease complications, the risk of developing bacteremia might also be genetically modulated. Accordingly, we studied the association of single nucleotide polymorphisms (SNPs) in candidate genes with the risk of bacteremia in sickle cell anemia. We found significant associations with SNPs in IGF1R and genes of the TGF-beta /BMP pathway (BMP6, TGFBR3, BMPR1A, SMAD6 and SMAD3). We suggest that both IGF1R and the TGF-beta /BMP pathway could play important roles in immune function in sickle cell anemia and their polymorphisms may help identify a "bacteremia-prone" phenotype.

Topics: Adolescent; Adult; Anemia, Sickle Cell; Bacteremia; Bone Morphogenetic Protein 6; Bone Morphogenetic Protein Receptors, Type I; Bone Morphogenetic Proteins; Child; Child, Preschool; Female; Genetic Predisposition to Disease; Humans; Linkage Disequilibrium; Male; Polymorphism, Genetic; Proteoglycans; Receptor, IGF Type 1; Receptors, Transforming Growth Factor beta; Smad3 Protein; Smad6 Protein; Transforming Growth Factor beta

We studied cytokine mRNA expression in Streptococcus pneumoniae carriage, pneumonia, and sepsis in 3-week-old, inbred C57BL/6 and BALB/c mice. Mice were inoculated intranasally with S. pneumoniae serotype 6B, 14, or 3. Survival, bacterial load in the nasopharynx (NP) and lungs, and mRNA levels of tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, interleukin (IL)-10, and IL-12 in the spleen were analyzed. No baseline mRNA expression levels were found, except for TNF-alpha in C57BL/6 mice. Serotype 6B caused NP colonization only, a significant (P<.05) increase in the levels of TNF-alpha, and induction of TGF-beta and IL-12 mRNA. Serotype 14 caused NP and nonlethal lung colonization and induction of TGF-beta, IL-10, and IL-12. Serotype 3 caused NP colonization, pneumonia, 35% mortality, and no alteration in the mRNA expression of tested cytokines. Although activation of the immune system culminated in nonlethal disease, evasion of the immune system was associated with detrimental disease.

Topics: Animals; Bacteremia; Carrier State; Cytokines; Interleukin-12; Lung; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Nasopharynx; Pneumonia, Pneumococcal; RNA, Messenger; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Sepsis is associated with depressed T-cell functions and increased circulating levels of immunosuppressive agents. TGF-beta is a potential anti-inflammatory cytokine that can modify T-cell growth and differentiation. The up-regulation of TGF-beta and the mechanism of its action on the T-cells during septic injury have not been resolved. We hypothesized that in sepsis TGF-beta produced by macrophages acts on T-cells in a paracrine manner to suppress interleukin (IL)-2 production and proliferation. In this study, we examined the circulating TGF-beta levels in a rat model of Gram-negative bacterial sepsis, and compared the abilities of adherent and non-adherent splenocytes to produce TGF-beta. Additionally, we investigated the causal relationships of hrTGF-beta to concanavalin A (ConA)-induced T-cell responses and the intracellular mechanism of the generation of these responses in normal splenic rat T-cells. Sepsis was induced in rats by intraabdominally implanting fecal pellets containing Escherichia coli (150 CFU) and Bacteroides fragilis (10000 CFU). Adherent and non-adherent splenocytes were isolated by differential adherence using Ficoll gradient centrifugation. T-cells were purified by use of Nylon wool columns. We observed a 3-6-fold increase in the circulating levels of TGF-beta in sepsis. Western blots and ELISA determinations revealed a 2.5-3-fold increase in cell-associated TGF-beta protein levels in adherent splenic cells. Northern analyses also showed a marked increase in TGF-beta mRNA expression in adherent cells during sepsis. On the other hand, a significant change was not observed in the TGF-beta protein and mRNA expression in non-adherent splenocytes. Pretreatment of control rat T-cells with hrTGF-beta decreased both ConA-induced proliferation (by 35-40%) and IL-2 mRNA expression (by > 50%). Further, whereas incubation of control rat T-cells with either ConA or TGF-beta for 24 h resulted in a 10-15-fold increase in cAMP generation, the addition of hrTGF-beta along with ConA resulted in a 50-60-fold increase in cAMP. These results suggest that in sepsis, TGF-beta produced by splenic macrophages can act in a paracrine manner on T-cells to depress their IL-2 mRNA expression, IL-2 production and proliferation after up-regulation of cAMP which can interfere with T-cell signaling for proliferation.

Topics: Animals; Bacteremia; Bacteroides fragilis; Bacteroides Infections; Cell Adhesion; Concanavalin A; Cyclic AMP; Enzyme-Linked Immunosorbent Assay; Escherichia coli Infections; Interleukin-2; Lymphocyte Activation; Male; Rats; Rats, Sprague-Dawley; Reference Values; Spleen; T-Lymphocytes; Transcription, Genetic; Transforming Growth Factor beta