We investigated the mechanisms by which T-cell cytokines are able to influence the Toll-like receptor (TLR)-induced, vitamin Ddependent antimicrobial pathway in human monocytes. T-cell cytokines differentially influenced TLR2/1-induced expression of the antimicrobial peptides cathelicidin and DEFB4, being upregulated by IFN-γ, down-regulated by IL-4, and unaffected by IL-17. The Th1 cytokine IFN-γ up-regulated TLR2/1 induction of 25-hydroxyvitamin D-1α-hydroxylase (i.e., CYP27B1), leading to enhanced bioconversion of 25-hydroxyvitamin D 3 (25D 3 ) to its active metabolite 1,25D 3 . In contrast, the Th2 cytokine IL-4, by itself and in combination with the TLR2/1 ligand, induced catabolism of 25D 3 to the inactive metabolite 24,25D 3 , and was dependent on expression of vitamin D-24-hydroxylase (i.e., CYP24A1). Therefore, the ability of T-cell cytokines to differentially control monocyte vitamin D metabolism represents a mechanism by which cell-mediated immune responses can regulate innate immune mechanisms to defend against microbial pathogens. Mycobacterium tuberculosisT he ability of Toll-like receptors (TLRs) to trigger a direct antimicrobial activity is a key aspect of their role in innate immunity. In mouse monocytes, activation of the TLR2/1 heterodimer by microbial lipoproteins (1-3), induces an antimicrobial activity against Mycobacterium tuberculosis that is nitric oxide (NO)-dependent, but in human monocytes is NO-independent (4). Instead, a key antimicrobial mechanism for TLR-activated human monocytes involves induction of the 25-hydroxyvitamin D-1α-hydroxylase (i.e., CYP27B1), which enzymatically converts the major circulating form of vitamin D, 25-hydroxyvitamin D3 (25D 3 ) into the active form of vitamin D, 1,25D 3 . Parallel TLRmediated up-regulation of the vitamin D receptor (VDR) and activation of this receptor by 1,25D 3 leads to downstream induction of the genes encoding the antimicrobial peptides cathelicidin and DEFB4 (5-10). Here, we tested the hypothesis that adaptive T-cell cytokines, including key cytokines of the Th1, Th2, and Th17 pattern, regulate the TLR2/1-induced, vitamin Ddependent antimicrobial pathway. ResultsEffect of T-Cell Cytokines on TLR2/1 Induction of Cathelicidin and DEFB4. To determine the role of individual cytokines on the TLRtriggered vitamin D-dependent induction of antimicrobial peptides, monocytes were treated with TLR2/1L with or without a specific T-cell cytokine, and cathelicidin and DEFB4 mRNAs measured at 24 h. IFN-γ by itself up-regulated cathelicidin and DEFB4 mRNA levels by twofold ( Fig. 1A; P < 0.05 and P < 0.001). Consistent with previous findings, TLR2/1L induced both cathelicidin and DEFB4 mRNAs (8, 10). However, whereas IFN-γ augmented TLR2/1L-triggered induction of cathelicidin by 4.1-fold (P < 0.01), it had no effect on TLR2/1L-mediated induction of DEFB4 (Fig. 1A). The addition of IL-17 had no effect on induction of antimicrobial peptide gene expression in the presence or absence of TLR2/1L (Fig. 1B).Whereas IFN-γ augmented TLR2/1 induction of cath...
Variability in bacterial sterilization is a key feature of Mycobacterium tuberculosis (Mtb) disease. In a population of human macrophages, there are macrophages that restrict Mtb growth and those that do not. However, the sources of heterogeneity in macrophage state during Mtb infection are poorly understood. Here, we perform RNAseq on restrictive and permissive macrophages and reveal that the expression of genes involved in GM-CSF signaling discriminates between the two subpopulations. We demonstrate that blocking GM-CSF makes macrophages more permissive of Mtb growth while addition of GM-CSF increases bacterial control. In parallel, we find that the loss of bacterial control that occurs in HIV-Mtb coinfected macrophages correlates with reduced GM-CSF secretion. Treatment of coinfected cells with GM-CSF restores bacterial control. Thus, we leverage the natural variation in macrophage control of Mtb to identify a critical cytokine response for regulating Mtb survival and identify components of the antimicrobial response induced by GM-CSF.
The periodontal pathogen T. denticola resides in a stressful environment rife with challenges, the human oral cavity. Knowledge of the stress response capabilities of this invasive spirochete is currently very limited. Whole genome expression profiles in response to different suspected stresses including heat shock, osmotic downshift, oxygen and blood exposure were examined. Most of the genes predicted to encode conserved heat shock proteins (HSPs) were found to be induced under heat and oxygen stress. Several of these HSPs also seem to be important for survival in hypotonic solutions and blood. In addition to HSPs, differential regulation of many genes encoding metabolic proteins, hypothetical proteins, transcriptional regulators and transporters was observed in patterns that could betoken functional associations. In summary, stress responses in T. denticola exhibit many similarities to the corresponding stress responses in other organisms but also employ unique components including the induction of hypothetical proteins.
Upon recognition of a microbial pathogen, the innate and adaptive immune systems are linked to generate a cell-mediated immune response against the foreign invader. The culture filtrate of contains ligands, such as tRNA, that activate the innate immune response and secreted Ags recognized by T cells to drive adaptive immune responses. In this study, bioinformatics analysis of gene-expression profiles derived from human PBMCs treated with distinct microbial ligands identified a mycobacterial tRNA-induced innate immune network resulting in the robust production of IL-12p70, a cytokine required to instruct an adaptive Th1 response for host defense against intracellular bacteria. As validated by functional studies, this pathway contained a feed-forward loop, whereby the early production of IL-18, type I IFNs, and IL-12p70 primed NK cells to respond to IL-18 and produce IFN-γ, enhancing further production of IL-12p70. Mechanistically, tRNA activates TLR3 and TLR8, and this synergistic induction of IL-12p70 was recapitulated by the addition of a specific TLR8 agonist with a TLR3 ligand to PBMCs. These data indicate that tRNA activates a gene network involving the integration of multiple innate signals, including types I and II IFNs, as well as distinct cell types to induce IL-12p70.
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