TLR4, but not TLR2, mediates IFN-β–induced STAT1α/β-dependent gene expression in macrophages

Toshchakov, Vladimir Y.; Jones, Bryan W.; Perera, Pin-Yu; Thomas, Karen E.; Cody, Michael J.; Zhang, Shuling; Williams, Bryan R.G.; Major, Jennifer; Hamilton, Thomas A.; Fenton, Matthew J.; Vogel, Stefanie N.

doi:10.1038/ni774

Cited by 757 publications

(766 citation statements)

References 37 publications

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“…This result is in agreement with studies showing that type I IFN are essential for TLR3-induced gene activation [39][40][41]. As an example, the production of IL-12 is highly reduced in IFNAR-deficient mice in response to TLR3/7 stimulation, suggesting that TLR engagement induces endogenous IFN that synergize for optimal IL-12 production [9].…”

Section: Discussionsupporting

confidence: 91%

PolyI:C plus IL‐2 or IL‐12 induce IFN‐γ production by human NK cells via autocrine IFN‐β

et al. 2009

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NK lymphocytes and type I IFN (IFN-a/b) are major actors of the innate anti-viral response that also influence adaptive immune responses. We evaluated type I IFN production by human NK cells in response to polyI:C, a potent type I IFN-inducing TLR3 agonist. PolyI:C plus IL-2/IL-12 induced IFN-b (but not IFN-a) mRNA expression and protein production by highly pure human NK cells and by the human NK cell line NK92. Neutralizing anti-IFNAR1 or anti-IFN-b Ab prevented the production of IFN-c induced by polyI:C plus IL-2/IL-12. Similarly, IFN-c production induced by polyI:C plus IL-12 was reduced in NK cells isolated from IFNAR1 À/À compared with WT mice. The ability of polyI:C plus IL-12 to induce IFN-c production was related to an increase of TLR3, Mda5 and IFNAR expression and by an increase of STAT1 and STAT4 phosphorylation. Collectively, these data demonstrate that NK cells, in response to polyI:C plus IL-2/IL-12, produce IFN-b that induce, in an autocrine manner, the production of IFN-c and thereby highlight that NK cells may control the outcome of protective or injurious immune responses through type I IFN secretion.Key words: IFN-g . NK cells . PolyI:C . Type I IFN IntroductionType I IFN is a multi-member cytokine family, in which IFN-a and -b are the main types of interest from an immunological perspective [1,2]. They are involved in anti-viral immunity and in some immune disorders (such as autoimmune diseases). In addition to directly interfering with viral replication, type I IFN have anti-proliferative and immunoregulatory properties. They bridge innate and adaptive immune responses by inducing DC maturation and favoring antigen cross-presentation [3]. They also act directly on CD8 1 T cells to favor the generation of effector and memory T cells [4]. The expression of type I IFN is induced early upon recognition of viruses or viral moieties by some innate receptors of the TLR or RIG-1-like receptor families [5]. IFN-a is mainly secreted by plasmacytoid DC in response to viral nucleic acids recognized by TLR7 and 9 [6]. IFN-b mRNA expression is induced in numerous cell types by TLR stimulation [7,8]. IFN-b has a short half-time, is difficult to quantify, and its secretion is mainly evidenced indirectly by neutralizing its activity in in vitro assay [9]. Owing to the central role of type I IFN in the [11]. These cells kill virally infected cells and tumoral cells in the absence of prior activation [11,12]. NK-cell cytotoxic activity is tightly regulated by inhibitory and activatory receptors [13]. Consequently, NK cells are important during the early phases of viral infection, while antigen-specific T-and B-cell responses are generated. In addition to cytotoxic properties, NK cells have immunoregulatory functions. Through the expression of cell surface molecules and the secretion of cytokines such as IFN-g, they directly modulate macrophages, B and T lymphocyte and DC functions [11,12,14,15]. Consequently, in addition to a protective role in anti-tumor and antiviral immunity, it is now suggested that NK c...

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Section: Discussionsupporting

confidence: 91%

PolyI:C plus IL‐2 or IL‐12 induce IFN‐γ production by human NK cells via autocrine IFN‐β

et al. 2009

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“…It was recently reported that LPS-induced expression of IFN-␤ mediates the phosphorylation of STAT1 in macrophages (Jacobs and Ignarro, 2001;Toshchakov et al, 2002), suggesting to us that PKR could play a role in LPS-induced IFN-␤ expression as an essential signal transducer. To test this possibility, we assayed the transcription pattern of IFN-␤ in LPSstimulated rat primary astrocyte.…”

Section: Pkr Is Required For Lps-stimulated Expression Of Ifn-␤ In Ramentioning

confidence: 88%

Double-stranded RNA-activated protein kinase is required for the LPS-induced activation of STAT1 inflammatory signaling in rat brain glial cells

Lee

Park

Kim

et al. 2005

Glia

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PKR, the double-stranded RNA (dsRNA)-activated serine/threonine kinase, has been implicated as an important component of host responses to infection and various situations of cellular stress. The involvement of PKR in signal transduction and regulation of transcription suggested to us that it may play an important role in lipopolysaccharide (LPS)-induced activation of STAT1 in rat brain immune cells. We found that LPS rapidly stimulated the phosphorylation of PKR within 5 min, followed by phosphorylation of STAT1 at 2 h in rat primary microglia and astrocyte. Using 2-aminopurine (2-AP), a pharmacological inhibitor of PKR, and PKR-specific short interfering RNA (siRNA), we demonstrated that activation of PKR was essential for LPS-induced activation of STAT1. Inhibition of PKR activity by 2-AP resulted in suppression not only of STAT1 phosphorylation, but also of nuclear factors binding activity to GAS/ISRE elements. 2-AP also significantly suppressed the downstream events of LPS-stimulated STAT1 phosphorylation, including STAT-mediated transcriptional responses and generation of nitric oxide, a hallmark of brain inflammation. Consistent with these results, transfection of PKR-specific siRNA markedly attenuated all the STAT1 dependent inflammatory signaling responses tested. We further revealed that activation of PKR by LPS led to the induction of IFN-␤ through activation of NF-B, triggering the phosphorylation of STAT1 in rat brain glial cells. Taken together, these findings indicate that PKR functions as an essential modulator in LPS-induced STAT inflammatory signaling events, and provides new insight into endotoxin-induced CNS diseases following infection.

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“…In vitro, costimulation of macrophages with IFN- § / g plus L. major led to a strong induction of iNOS [24]. LPS plus IFN- § / g or LPS alone (which requires endogenously produced IFN- § / g for the induction of iNOS [25,26]) activated wild-type, but not Tyk2 -/-peritoneal exudate macrophages for the production of NO [17] (Fig. 8A).…”

Section: Tyk2 and The Expression Of Inosmentioning

confidence: 95%

“…The lysates (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) ? g protein/lane) were separated by 7.5% SDS-PAGE, transferred to reinforced nitrocellulose (0.45 ?…”

Section: Sds-page Western Blotting and Immunoprecipitationmentioning

confidence: 99%

Control of Leishmania major in the absence of Tyk2 kinase

et al. 2004

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IL‐12 is indispensable for the control of many intracellular pathogens, but the components of the signaling pathway that are essential for its function in vivo are incompletely understood. Here, we investigated in the Leishmania major mouse model whether Tyk2 kinase is required for the generation of a protective immune response. Unlike C57BL/6 controls, Tyk2–/–mice developed severe skin lesions after infection that frequently ulcerated, but ultimately healed. NK cell cytotoxicity was absent in infected Tyk2–/– mice, even after IL‐12 pretreatment, which correlated with a STAT4 activation defect. IFN‐α / β, which was still able to activate STAT1 in Tyk2–/– NK cells, reconstituted their cytotoxic activity, but not their IL‐12responsiveness. The IL‐12‐induced production of IFN‐γ by NK cells and CD8+ T cells was strongly suppressed in Tyk2–/– mice at day 1 of infection, but partly regained during the late phase of infection. Tyk2–/– CD4+ T cells developed into Th1 cells (although in a delayed fashion) and infected Tyk2–/– mice expressed normals levels of inducible NO synthase. Thus, Tyk2 is required for the IL‐12 response of NK cells and CD8+ T cells in L. major‐infected mice, but not for the generation of Th1 cells and the ultimate control of the disease.

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TLR4, but not TLR2, mediates IFN-β–induced STAT1α/β-dependent gene expression in macrophages

Cited by 757 publications

References 37 publications

PolyI:C plus IL‐2 or IL‐12 induce IFN‐γ production by human NK cells via autocrine IFN‐β

PolyI:C plus IL‐2 or IL‐12 induce IFN‐γ production by human NK cells via autocrine IFN‐β

Double-stranded RNA-activated protein kinase is required for the LPS-induced activation of STAT1 inflammatory signaling in rat brain glial cells

Control of Leishmania major in the absence of Tyk2 kinase

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