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  • The American Association of Immunologists  (5)
  • 1
    Online Resource
    Online Resource
    IL-17 Suppresses Immune Effector Functions in Human Papillomavirus-Associated Epithelial Hyperplasia
    The American Association of Immunologists ; 2014
    In:  The Journal of Immunology Vol. 193, No. 5 ( 2014-09-01), p. 2248-2257
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 193, No. 5 ( 2014-09-01), p. 2248-2257
    Abstract: Persistent infection with high-risk human papillomaviruses (HPV) causes epithelial hyperplasia that can progress to cancer and is thought to depend on immunosuppressive mechanisms that prevent viral clearance by the host. IL-17 is a cytokine with diverse functions in host defense and in the pathology of autoimmune disorders, chronic inflammatory diseases, and cancer. We analyzed biopsies from patients with HPV-associated cervical intraepithelial neoplasia grade 2/3 and murine skin displaying HPV16 E7 protein-induced epithelial hyperplasia, which closely models hyperplasia in chronic HPV lesions. Expression of IL-17 and IL-23, a major inducer of IL-17, was elevated in both human HPV-infected and murine E7-expressing lesions. Using a skin-grafting model, we demonstrated that IL-17 in HPV16 E7 transgenic skin grafts inhibited effective host immune responses against the graft. IL-17 was produced by CD3+ T cells, predominantly CD4+ T cells in human, and CD4+ and γδ T cells in mouse hyperplastic lesions. IL-23 and IL-1β, but not IL-18, induced IL-17 production in E7 transgenic skin. Together, these findings demonstrate an immunosuppressive role for IL-17 in HPV-associated epithelial hyperplasia and suggest that blocking IL-17 in persistent viral infection may promote antiviral immunity and prevent progression to cancer.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1400216
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2014
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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    Online Resource
  • 2
    Online Resource
    Online Resource
    Expression of Many Immunologically Important Genes in Mycobacterium tuberculosis -Infected Macrophages Is Independent of Both TLR2 and TLR4 but Dependent on IFN-αβ Receptor and STAT1
    The American Association of Immunologists ; 2005
    In:  The Journal of Immunology Vol. 175, No. 5 ( 2005-09-01), p. 3318-3328
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 175, No. 5 ( 2005-09-01), p. 3318-3328
    Abstract: Macrophages respond to several subcellular products of Mycobacterium tuberculosis (Mtb) through TLR2 or TLR4. However, primary mouse macrophages respond to viable, virulent Mtb by pathways largely independent of MyD88, the common adaptor molecule for TLRs. Using microarrays, quantitative PCR, and ELISA with gene-disrupted macrophages and mice, we now show that viable Mtb elicits the expression of inducible NO synthase, RANTES, IFN-inducible protein 10, immune-responsive gene 1, and many other key genes in macrophages substantially independently of TLR2, TLR4, their combination, or the TLR adaptors Toll-IL-1R domain-containing adapter protein and Toll-IL-1R domain-containing adapter inducing IFN-β. Mice deficient in both TLR2 and TLR4 handle aerosol infection with viable Mtb as well as congenic controls. Viable Mtb also up-regulates inducible NO synthase, RANTES, IFN-inducible protein 10, and IRG1 in macrophages that lack mannose receptor, complement receptors 3 and 4, type A scavenger receptor, or CD40. These MyD88, TLR2/4-independent transcriptional responses require IFN-αβR and STAT1, but not IFN-γ. Conversely, those genes whose expression is MyD88 dependent do not depend on IFN-αβR or STAT1. Transcriptional induction of TNF is TLR2/4, MyD88, STAT1, and IFN-αβR independent, but TNF protein release requires the TLR2/4-MyD88 pathway. Thus, macrophages respond transcriptionally to viable Mtb through at least three pathways. TLR2 mediates the responses of a numerically minor set of genes that collectively do not appear to affect the course of infection in mice; regulation of TNF requires TLR2/4 for post-transcriptional control, but not for transcriptional induction; and many responding genes are regulated through an unknown, TLR2/4-independent pathway that may involve IFN-αβR and STAT1.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.175.5.3318
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2005
    detail.hit.zdb_id: 1475085-5
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  • 3
    Online Resource
    Online Resource
    SPATIOTEMPORAL REGULATION OF RP105 SUBCELLULAR LOCALIZATION SHAPES ENDOSOMAL TLR4 SIGNALING
    The American Association of Immunologists ; 2023
    In:  The Journal of Immunology Vol. 210, No. 1_Supplement ( 2023-05-01), p. 160.06-160.06
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 210, No. 1_Supplement ( 2023-05-01), p. 160.06-160.06
    Abstract: Innate immune sensing of microbial and endogenous ligands by Toll-like receptor (TLR) 4 drives inflammation and antimicrobial mechanisms. While critical for host defense against pathogens, unchecked TLR4 activation causes organ damage and chronic disease. Molecular mechanisms that drive versus turn off TLR4 activity are being pursued as potential targets for preventing and treating infections and inflammation-driven pathologies. Mechanisms of the temporal and spatial regulation of TLR4 signaling originating from the cell surface are well established. In contrast, the regulation of TLR4 activation originating from endosomal compartments is not well known. Here we show that the TLR-related receptor, Radioprotective 105 kDa (RP105), localizes to TLR4-containing endosomal compartments in murine macrophages. RP105 has been proposed as a negative regulator of TLR4-MyD88 signaling originating from the cell surface, but whether it modulates endosomal TLR4 signaling is unknown. Our data shows that RP105-deficiency reduces LPS- and E. coli-induced type I IFN responses, suggesting that RP105 facilitates endosomal TLR4-TRIF signaling. We employed high-resolution microscopy and AI-guided quantitative analyses to interrogate the spatiotemporal relationship between RP105 and endosomal compartments. Cellular activation led to a transient reduction of RP105 from endosomal compartments. Our results suggest TLR4 activation via TRIF signaling mediates this process, but not MyD88. Moreover, our data identify phosphatidylinositol 3-kinase p110-delta and Bruton’s tyrosine kinase as critical regulators of RP105 endosomal localization. Collectively, our data identify RP105 as a positive regulator of endosomal TLR4 signaling. AAI Careers in Immunology Fellowship, 2022-2023
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.210.Supp.160.06
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2023
    detail.hit.zdb_id: 1475085-5
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  • 4
    Online Resource
    Online Resource
    RP105 Engages Phosphatidylinositol 3-Kinase p110δ To Facilitate the Trafficking and Secretion of Cytokines in Macrophages during Mycobacterial Infection
    The American Association of Immunologists ; 2015
    In:  The Journal of Immunology Vol. 195, No. 8 ( 2015-10-15), p. 3890-3900
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 195, No. 8 ( 2015-10-15), p. 3890-3900
    Abstract: Cytokines are key regulators of adequate immune responses to infection with Mycobacterium tuberculosis. We demonstrate that the p110δ catalytic subunit of PI3K acts as a downstream effector of the TLR family member RP105 (CD180) in promoting mycobacteria-induced cytokine production by macrophages. Our data show that the significantly reduced release of TNF and IL-6 by RP105−/− macrophages during mycobacterial infection was not accompanied by diminished mRNA or protein expression. Mycobacteria induced comparable activation of NF-κB and p38 MAPK signaling in wild-type (WT) and RP105−/− macrophages. In contrast, mycobacteria-induced phosphorylation of Akt was abrogated in RP105−/− macrophages. The p110δ-specific inhibitor, Cal-101, and small interfering RNA–mediated knockdown of p110δ diminished mycobacteria-induced TNF secretion by WT but not RP105−/− macrophages. Such interference with p110δ activity led to reduced surface-expressed TNF in WT but not RP105−/− macrophages, while leaving TNF mRNA and protein expression unaffected. Activity of Bruton’s tyrosine kinase was required for RP105-mediated activation of Akt phosphorylation and TNF release by mycobacteria-infected macrophages. These data unveil a novel innate immune signaling axis that orchestrates key cytokine responses of macrophages and provide molecular insight into the functions of RP105 as an innate immune receptor for mycobacteria.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1500017
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2015
    detail.hit.zdb_id: 1475085-5
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  • 5
    Online Resource
    Online Resource
    Mycobacteria-Induced TNF-α and IL-10 Formation by Human Macrophages Is Differentially Regulated at the Level of Mitogen-Activated Protein Kinase Activity
    The American Association of Immunologists ; 2001
    In:  The Journal of Immunology Vol. 167, No. 6 ( 2001-09-15), p. 3339-3345
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 167, No. 6 ( 2001-09-15), p. 3339-3345
    Abstract: The clinical course of mycobacterial infections is linked to the capacity of pathogenic strains to modulate the initial antimycobacterial response of the macrophage. To elucidate some of the mechanisms involved, we studied early signal transduction events leading to cytokine formation by human monocyte-derived macrophages (MDM) in response to clinical isolates of Mycobacterium avium. TNF-α production induced by M. avium was inhibited by anti-CD14 mAbs, but not by Abs against the macrophage mannose receptor. Analysis of mitogen-activated protein (MAP) kinase activation (extracellular signal-regulated kinase 1/2, p38, and c-Jun NH2-terminal kinase) showed a rapid phosphorylation of all three subfamilies in response to M. avium, which was inhibited by anti-CD14 Abs. Using highly specific inhibitors of p38 (SB203580) and MAP kinase kinase-1 (PD98059), we found that activation of the extracellular signal-regulated kinase pathway, but not of p38, was essential for the M. avium-induced TNF-α formation. In contrast, IL-10 production was abrogated by the p38 inhibitor, but not by the MAP kinase kinase-1 inhibitor. In conclusion, M. avium-induced secretion of TNF-α and IL-10 by human macrophages is differentially regulated at the level of MAP kinase activity.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.167.6.3339
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2001
    detail.hit.zdb_id: 1475085-5
    Location Call Number Limitation Availability
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