Induction of Cytokines in Cynomolgus Monkeys by the Immune Response Modifiers, Imiquimod, S-27609 and S-28463

Wagner, Tamara L.; Horton, Vicki L.; Carlson, Gary; Myhre, Paula E.; Gibson, Sheila J.; Imbertson, Linda M.; Tomai, Mark A.

doi:10.1006/cyto.1997.0239

Cited by 74 publications

(51 citation statements)

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“…The 3M compound S-27609 is an IRM (41,43,54,55) and induces NF-B nuclear localization by signaling through TLR7 (Fig. 1), similar to other 3 M antiviral compounds such as imiquimod and resiquimod (R848) (48,49).…”

Section: The Irm S-27609 Is a Tlr7 Agonist And Induces Tnf-␣ And Il-1mentioning

confidence: 63%

The Immune Response Modifier and Toll-Like Receptor 7 Agonist S-27609 Selectively Induces IL-12 and TNF-α Production in CD11c+CD11b+CD8− Dendritic Cells

Doxsee¹,

Riter²,

Reiter³

et al. 2003

The Journal of Immunology

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IL-12 and TNF-α production by dendritic cells (DCs) is a critical step in the initiation of local inflammation and adaptive immune responses. We show in this study that a small molecule immune response modifier that is a Toll-like receptor 7 (TLR7) agonist induces IL-12 and TNF-α production from murine CD11c+CD11b+CD8− DCs, a subset not previously known for this activity. Stimulation of these DCs through TLR7 in vivo induces significant cytokine production even 12 h after initial stimulation, as well as migration of the DC into T cell zones of the lymphoid tissue. In contrast, stimulation through TLR4 and TLR9 induced IL-12 production predominantly from CD8+ DCs, consistent with previously published data. All TLR stimuli induced the increase in surface expression of the activation markers B7-1, B7-2, and class II in both CD8+ and CD8− DCs, demonstrating that CD8+ DCs do respond to TLR7-mediated stimuli. To date this is the only known stimuli to induce preferential cytokine production from CD8− DCs. Given the efficacy of TLR7 agonists as antiviral agents, the data collectively indicate that stimulation of CD8− DCs through TLR7 most likely plays a role in the generation of antiviral immune responses.

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Section: The Irm S-27609 Is a Tlr7 Agonist And Induces Tnf-␣ And Il-1mentioning

confidence: 63%

The Immune Response Modifier and Toll-Like Receptor 7 Agonist S-27609 Selectively Induces IL-12 and TNF-α Production in CD11c+CD11b+CD8− Dendritic Cells

Doxsee¹,

Riter²,

Reiter³

et al. 2003

The Journal of Immunology

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“…To name but a few, imiquimod induces expression of proinflammatory cytokines including IFNa, TNFa, IL-2, -6, -8, -12, G-CSF and GM-CSF, as well as chemokines such as CCL3 (MIP-1a), CCL4 (MIP-1b) and CCL2 (MCP-1) (Reiter et al, 1994;Weeks and Gibson, 1994;Gibson et al, 1995;Megyeri et al, 1995;Wagner et al, 1997). In addition to the NF-kBmediated transcription of proinflammatory mediators, it appears that TLR-7-(and TLR-8)-agonistic activities of imiquimod induce some proinflammatory cytokines, such as IFNg, in a NF-kB-independent fashion.…”

Section: Tlr7 and Tlr8 As Targets In Cancer Therapymentioning

confidence: 99%

“…Resiquimod induces more pronounced cytokine secretion, macrophage activation and enhancement of cellular immunity as compared to imiquimod (Wagner et al, 1997(Wagner et al, , 1999Imbertson et al, 1998;Bernstein et al, 2000;Burns et al, 2000).…”

mentioning

confidence: 98%

TLR7 and TLR8 as targets in cancer therapy

2008

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Small-molecule agonists at Toll-like receptor 7 (TLR7) and TLR8 have sparked a vivid interest in cancer research owing to their profound antitumoral activity. The lead compound of the imidazoquinoline family, imiquimod, is marketed as a topical formulation. It is efficacious against many primary skin tumors and cutaneous metastases. Using different imidazoquinoline species, distinct functions of TLR7 and TLR8 have been discovered. The predominant antitumoral mode of action of these agents is TLR7/ 8-mediated activation of the central transcription factor nuclear factor-jB, which leads to induction of proinflammatory cytokines and other mediators. Cutaneous dendritic cells are the primary responsive cell type and initiate a strong Th1-weighted antitumoral cellular immune response. Recent research has shown that dendritic cells themselves acquire direct antitumoral activity upon stimulation by imiquimod. In addition, there are a number of secondary effects on the molecular and cellular level that can be explained through the activation of TLR7/8. The proinflammatory activity of imiquimod, but not resiquimod, appears to be augmented by suppression of a regulatory mechanism, which normally limits inflammatory responses. This is achieved independently of TLR7/8 through interference with adenosine receptor signaling pathways. Finally, at higher concentrations imiquimod exerts Bcl-2-and caspase-dependent proapoptotic activity against tumor cells.

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“…The differential pattern of immunologically relevant genes activated in macrophages during infection with NS4B.VGIv and BICv resembled that induced by a well-characterized compound that stimulates macrophage activity, imiquimod R837 (I-R837) (5,11,12,21,45,49). I-R837, an imidazoquinoline amine analog to guanosine, is an immune response modifier with potent indirect antiviral activity (5).…”

Section: Resultsmentioning

confidence: 96%

“…Interestingly, most of the genes showing increased transcriptional activation upon NS4B.VGIv infection are also induced by activated TLR-7 (1,18,19), suggesting NS4B-mediated interference with TLR-7 activity during infection with virulent wild-type virus. The transient expression of wild-type NS4B, but not of the NS4B gene harboring mutations in either of the putative boxes, interfered with the transcriptional activation of TLR-7-induced immuneregulatory genes (e.g., IL-6) in swine macrophages treated with a TLR-7 activator, imiquimod R837 (I-R837) (5,11,15,21,45,49). In vivo analyses demonstrated significantly higher levels of IL-6 that were maintained in the tonsils of swine experimentally infected with NS4B.VGIv than in those of swine infected with BICv.…”

mentioning

confidence: 99%

Mutations in Classical Swine Fever Virus NS4B Affect Virulence in Swine

Fernandez-Sainz

Gladue

Holinka

et al. 2010

J Virol

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NS4B is one of the nonstructural proteins of classical swine fever virus (CSFV), the etiological agent of a severe, highly lethal disease of swine. Protein domain analysis of the predicted amino acid sequence of the NS4B protein of highly pathogenic CSFV strain Brescia (BICv) identified a putative Toll/interleukin-1 receptor (TIR)-like domain. This TIR-like motif harbors two conserved domains, box 1 and box 2, also observed in other members of the TIR superfamily, including Toll-like receptors (TLRs). Mutations within the BICv NS4B box 2 domain (V2566A, G2567A, I2568A) produced recombinant virus NS4B.VGIv, with an altered phenotype displaying enhanced transcriptional activation of TLR-7-induced genes in swine macrophages, including a significant sustained accumulation of interleukin-6 (IL-6) mRNA. Transfection of swine macrophages with the wild-type NS4B gene partially blocked the TLR-7-activating effect of imiquimod (R837), while transfection with the NS4B gene harboring mutations in either of the putative boxes displayed decreased blocking activity. NS4B.VGIv showed an attenuated phenotype in swine, displaying reduced replication in the oronasal cavity and limited spread from the inoculation site to secondary target organs. Furthermore, the level and duration of IL-6 production in the tonsils of pigs intranasally inoculated with NS4B.VGIv were significantly higher than those for animals infected with BICv. The peak of IL-6 production in infected animals paralleled the ability of animals infected with NS4B.VGIv to resist challenge with virulent BICv. Interestingly, treatment of peripheral blood mononuclear cell cultures with recombinant porcine IL-6 results in a significant decrease in BICv replication.

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Induction of Cytokines in Cynomolgus Monkeys by the Immune Response Modifiers, Imiquimod, S-27609 and S-28463

Cited by 74 publications

References 0 publications

The Immune Response Modifier and Toll-Like Receptor 7 Agonist S-27609 Selectively Induces IL-12 and TNF-α Production in CD11c+CD11b+CD8− Dendritic Cells

The Immune Response Modifier and Toll-Like Receptor 7 Agonist S-27609 Selectively Induces IL-12 and TNF-α Production in CD11c+CD11b+CD8− Dendritic Cells

TLR7 and TLR8 as targets in cancer therapy

Mutations in Classical Swine Fever Virus NS4B Affect Virulence in Swine

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