Interleukin-1β induces<i>in vivo</i>tolerance to lipopolysaccharide in mice

Alves-Rosa, Fernanda; Vulcano, Marisa; Beigier-Bompadre, Macarena; Fernández, Gabriela; Palermo, Marina S.; Isturiz, Martı́n A.

doi:10.1046/j.1365-2249.2002.01828.x

Cited by 48 publications

(48 citation statements)

References 39 publications

(50 reference statements)

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“…Cross tolerance among different TLRs, which share the MyD88 signaling pathway, has been reported (27)(28)(29). Hence, we tested whether TLR7 agonist pretreatment could induce in vivo tolerance to other TLR agonists.…”

Section: Tlr7-induced Tolerance Resulted In Hyporesponsiveness To Othermentioning

confidence: 98%

Prevention of autoimmune disease by induction of tolerance to Toll-like receptor 7

Hayashi¹,

Gray²,

Chan³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

101

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Activation of Toll-like receptors (TLR) contributes to the initiation and maintenance of chronic inflammation in autoimmune diseases, yet repeated exposure to a TLR agonist can induce hyporesponsiveness to subsequent TLR stimulation. Here, we used a synthetic TLR7 agonist, 9-benzyl-8-hydroxy-2-(2-methoxyethoxy) adenine (SM360320, 1V136) to study TLR7 induced attenuation of inflammatory responses and its application to autoimmune diseases. Repeated low dose administration of this TLR7 agonist induced hyporesponsiveness or tolerance to TLR2, -7, and -9 activators and limited the course of neural inflammation in an experimental allergic encephalomyelitis model. The hyporesponsiveness did not depend on T or B lymphocytes, but did require bone marrow derived cells. In addition, TLR7 tolerance reduced inflammation in a passive antibody mediated arthritis model. TLR7 tolerance did not cause global immunosuppression, because susceptibility to Listeria monocytogenes infection was not altered. The mechanism of TLR7 tolerance involved the up-regulation of 2 inhibitors of TLR signaling: Interleukin 1 Receptor Associated Kinase (IRAK) M, and Src homology 2 domain-containing inositol polyphosphate phosphatase (SHIP)-1. These findings suggest that induction of TLR7 tolerance might be a new therapeutic approach to subdue inflammation in autoimmune diseases.arthritis ͉ encephalomyelitis ͉ synthetic agonist

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Section: Tlr7-induced Tolerance Resulted In Hyporesponsiveness To Othermentioning

confidence: 98%

Prevention of autoimmune disease by induction of tolerance to Toll-like receptor 7

Hayashi¹,

Gray²,

Chan³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

101

View full text Add to dashboard Cite

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“…In in vitro systems, in the absence of immunosuppressive circuits, recombinant IL-1␤ can be immunostimulatory, as recently shown by its ability to costimulate IFN-␥ production by T cells or NK cells (30,31). In contrast, repeated exposure of macrophages to IL-1␤ renders them tolerant to cytokine secretion in response to further inflammatory stimuli (32). This may occur in the vicinity of IL-1␤-transfected tumors that continuously secrete the cytokine.…”

Section: Discussionmentioning

confidence: 99%

Differential Effects of IL-1α and IL-1β on Tumorigenicity Patterns and Invasiveness

Song

Voronov

Dvorkin

et al. 2003

The Journal of Immunology

154

150

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In this study, we show that distinct compartmentalization patterns of the IL-1 molecules (IL-1α and IL-1β), in the milieu of tumor cells that produce them, differentially affect the malignant process. Active forms of IL-1, namely precursor IL-1α (pIL-1α), mature IL-1β (mIL-1β), and mIL-1β fused to a signal sequence (ssIL-1β), were transfected into an established fibrosarcoma cell line, and tumorigenicity and antitumor immunity were assessed. Cell lines transfected with pIL-1α, which expresses IL-1α on the membrane, fail to develop local tumors and activate antitumor effector mechanisms, such as CTLs, NK cells, and high levels of IFN-γ production. Cells transfected with secretable IL-1β (mIL-1β and ssIL-1β) were more aggressive than wild-type and mock-transfected tumor cells; ssIL-1β transfectants even exhibited metastatic tumors in the lungs of mice after i.v. inoculation (experimental metastasis). In IL-1β tumors, increased vascularity patterns were observed. No detectable antitumor effector mechanisms were observed in spleens of mice injected with IL-1β transfectants, mock-transfected or wild-type fibrosarcoma cells. Moreover, in spleens of mice injected with IL-1β transfectants, suppression of polyclonal mitogenic responses (proliferation, IFN-γ and IL-2 production) to Con A was observed, suggesting the development of general anergy. Histologically, infiltrating mononuclear cells penetrating the tumor were seen at pIL-1α tumor sites, whereas in mIL-1β and ssIL-1β tumor sites such infiltrating cells do not penetrate inside the tumor. This is, to our knowledge, the first report on differential, nonredundant, in vivo effects of IL-1α and IL-1β in malignant processes; IL-1α reduces tumorigenicity by inducing antitumor immunity, whereas IL-1β promotes invasiveness, including tumor angiogenesis, and also induces immune suppression in the host.

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“…As many of our patients have no known LPS exposure associated with the development of immunoparalysis, it seems unlikely that this accounts for most episodes of innate immune dysfunction in the ICU. Possible intracellular mechanisms that have been associated with models of endotoxin tolerance include inhibition of the proinflammatory transcription factor NFκB through either alteration of its subunit composition [40,41] or upregulation of its inhibitor IκBα [42]; upregulation of the NFκB pathway inhibitor IRAK-M [43][44][45]; or impairment of TLR4 signaling [46][47][48].…”

Section: Mechanisms Of Immunoparalysismentioning

confidence: 99%