IL‐18 enhances IFN‐γ‐induced production of CXCL9, CXCL10, and CXCL11 in human keratinocytes

Kanda, Naoko; Shimizu, Teruo; Tada, Yayoi; Watanabe, Shinichi

doi:10.1002/eji.200636420

Cited by 154 publications

(134 citation statements)

References 52 publications

(54 reference statements)

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“…Although the mechanism is unknown, a potential candidate is IFN regulatory factor 1 (IRF-1). Activation of TLRs can directly induce IRF-1 expression (75), which in turn can transcriptionally control expression of the genes for CXCL9, CXCL10, and CXCL11 (76,77). Moreover, IRF-1 expression was shown to be essential for expression of CXCL11 and suppression of pulmonary metastases by CXCR3-expressing NK cells (78).…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8 ⁺ T-cell axis

Brackett

Kojouharov

Veith

et al. 2016

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

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Activation of an anticancer innate immune response is highly desirable because of its inherent ability to generate an adaptive antitumor T-cell response. However, insufficient safety of innate immune modulators limits clinical use to topical applications. Tolllike receptor 5 (TLR5) agonists are favorably positioned as potential systemic immunotherapeutic agents because of unusual tissue specificity of expression, uniquely safe profile of induced cytokines, and antitumor efficacy demonstrated in a number of animal models. Here, we decipher the molecular and cellular events underlying the metastasis suppressive activity of entolimod, a clinical stage TLR5 agonist that activates NF-κB-, AP-1-, and STAT3-driven immunomodulatory signaling pathways specifically within the liver. Used as a single agent in murine colon and mammary metastatic cancer models, entolimod rapidly induces CXCL9 and -10 that support homing of blood-borne CXCR3-expressing NK cells to the liver predominantly through an IFN-γ signaling independent mechanism. NK cell-dependent activation of dendritic cells is followed by stimulation of a CD8 + T-cell response, which exert both antimetastatic effect of entolimod and establishment of tumor-specific and durable immune memory. These results define systemically administered TLR5 agonists as organ-specific immunoadjuvants, enabling efficient antitumor vaccination that does not depend on identification of tumor-specific antigens.cancer immunotherapy | liver | colorectal cancer | breast cancer | innate immunity R ecent advancements in the field of anticancer immunotherapy have been primarily focused on development of T-cellbased approaches because of recognition of the inherent ability of adaptive immunity to efficiently eradicate neoplastic disease (1, 2). Innate immune responses play important roles in T-cell activation, but their potential relevance for prevention and treatment of cancer remains underappreciated (3-5). Toll-like receptors (TLRs) are gaining attention as potential therapeutic targets capable of stimulating antitumor immunity by initiating innate responses (6) and subsequent adaptive T-cell-based immunity (7). Although proof-ofprinciple for this concept has been demonstrated with agonists of several TLRs (TLR3, -7, and -9) (8), only one, the TLR7 agonist Imiquimod, has been approved for clinical use [however, this is limited to topical treatment of basal cell carcinoma (9)]. The major clinical limitations of many TLR agonists are the risk of dose-limiting toxicities associated with their systemic delivery (10-12) and metastasis stimulation (13-15). Furthermore, some previously investigated TLR agonists are restricted to injection directly into tumor tissue (3,(16)(17)(18), an approach that will likely have limited therapeutic value in cancer patients with metastatic disease.TLR5 is unique among TLRs as a potential target for systemic anticancer immunotherapy. Studies have shown that the only known natural TLR5 agonist, flagellin, flagellin-expressing Salmonella bacteria, and a pharmacolog...

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Section: Discussionmentioning

confidence: 99%

Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8 ⁺ T-cell axis

Brackett

Kojouharov

Veith

et al. 2016

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

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“…22,23 CXCL9, CXCL10, and CXCL11 have been implicated in type 1 T helper cell recruitment to inflamed skin during psoriasis and dermatitis. 24 These are only three examples of diseases with chemokine-mediated cell recruitment and inflammation, but chemokines and chemokine receptors are involved in a large variety of pathologies, such as atherosclerosis, asthma, Crohn's disease, bacterial pneumonia, acute respiratory distress syndrome, bacterial or viral meningitis, sarcoidosis, and tuberculoid leprosy, as well as a wide variety of neurological diseases (addressed later in this review).…”

Section: Pleiotropic Functions Of Chemokines and Chemokine Receptorsmentioning

confidence: 99%

Chemokines and Chemokine Receptors in Neurological Disease: Raise, Retain, or Reduce?

Savarin-Vuaillat¹,

Ransohoff²

2007

Neurotherapeutics

156

126

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Summary:Chemokines and chemokine receptors comprise a large number of molecules implicated in a wide range of physiological and pathological functions. Numerous studies have demonstrated the roles of chemokines and chemokine receptors: 1) during development, by regulating hematopoiesis, cardiogenesis, and vascular and cerebellar development; 2) during tumor biology, by controlling cell proliferation, angiogenesis, and metastasis; and 3), especially during leukocyte migration, by acting on firm adhesion, locomotion, diapedesis, and chemotaxis. This review focuses on chemokine and chemokine receptor involvement in diverse neurological diseases and their therapeutic potentials. Because of its induction or upregulation during CNS pathologies, members of the chemokine system can be used as biological markers. CXCR4 and CXCL12, by the correlation between their expression and the glioblastoma tumor progression, could be a marker to grade this type of CNS tumor. CCR1, by virtue of specific expression in A␤ plaques, may be a marker for Alzheimer pathology. Downregulation of CCL2 in cerebrospinal fluid may be a candidate to characterize multiple sclerosis (MS), but needs additional investigation. Moreover, chemokines and chemokine receptors represent interesting therapeutic targets. Using chemokine receptor antagonists, several studies provided exciting findings for potential neurological disease treatment. Chemokine receptor antagonists reduce disease severity in animal models of MS. In glioblastoma, a CXCR4 antagonist (AMD3100) showed an inhibition of tumor growth. Inhibition of chemokine receptor signaling is not the only therapeutic strategy: for example, CXCR4 -CXCL12 has anti-inflammatory properties and CX3CL1-CX3CR1 controls neurotoxicity. Thus, chemokine biology suggests several approaches for treating neurological disease.

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“…Total cellular RNAwas extracted and reverse-transcribed to produce cDNA. The cDNA was thermocycled for PCR by using specific primers, as described previously [42,43]. PCR was performed by 1 denaturing cycle of 95 C for 3 min; 25 cycles of denaturation at 95 C for 30 s, annealing at 58 C for 30 s, and extension at 72 C for 30 s; and a final extension at 72 C for 3 min.…”

Section: Rt-pcrmentioning

confidence: 99%

“…Transient transfection was performed using Fugene 6 (Roche, Indianapolis, IN) as described previously [42]. The keratinocytes were plated in 35-mm dishes and grown to approximately 60% confluence.…”

Section: Plasmid and Transfectionmentioning

confidence: 99%

“…Antisense oligonucleotides against NF-jB p50, NF-jB p65, STAT1, STAT3, and control scrambled oligonucleotides were synthesized by phosphoroamidite chemistry, as described previously [42,47,48]. The keratinocytes were transfected with the indicated oligonucleotides (each 0.2 lM) premixed with Fugene 6 in KGM for 6 h. The cells were treated with high-calcium KBM for 48 h, and then incubated with 10 ng/mL IL-1b and/or the indicated concentrations of IL-12, IL-23, or IL-27.…”

Section: Treatment With Antisense Oligonucleotidesmentioning

confidence: 99%

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IL‐12, IL‐23, and IL‐27 enhance human β‐defensin‐2 production in human keratinocytes

Kanda¹,

Watanabe²

2008

Eur J Immunol

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IL-12, IL-23, and IL-27, which are produced by APC, modulate innate and adaptive immunities. Human b-defensin-2 (hBD-2) produced by epidermal keratinocytes promotes cutaneous antimicrobial defense and inflammation. We examined the in vitro effects of IL-12, IL-23, and IL-27 on hBD-2 production in human keratinocytes. IL-12, IL-23, and IL-27 enhanced IL-1b-induced hBD-2 secretion and mRNA expression in keratinocytes. The stimulatory effects of IL-12, IL-23, and IL-27 were suppressed by antisense oligonucleotides against NF-jB p50 and p65. In addition, the effects of IL-12 and IL-27 were suppressed by antisense STAT3 and STAT1, respectively. All the three IL enhanced the basal and IL-1b-induced transcriptional activities of NF-jB, while IL-12 and IL-27 enhanced STAT3 and STAT1 activities, respectively. Further, IL-12, IL-23, and IL-27 promoted basal and IL-1b-induced phosphorylation of IjBa. IL-12 and IL-23 tyrosine phosphorylated STAT3 and STAT1, respectively; IL-12, IL-23, and IL-27 tyrosine phosphorylated JAK2 and tyrosine kinase-2; and IL-27 tyrosine phosphorylated JAK1. These results suggest that IL-12, IL-23, and IL-27 may enhance IL-1b-induced hBD-2 production in keratinocytes by activating NF-jB. STAT3 and STAT1 are involved in the effects of IL-12 and IL-27, respectively. Thus, IL-12, IL-23, and IL-27 may promote cutaneous antimicrobial defense and inflammation via hBD-2.

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IL‐18 enhances IFN‐γ‐induced production of CXCL9, CXCL10, and CXCL11 in human keratinocytes

Cited by 154 publications

References 52 publications

Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8 ⁺ T-cell axis

Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8 ⁺ T-cell axis

Chemokines and Chemokine Receptors in Neurological Disease: Raise, Retain, or Reduce?

IL‐12, IL‐23, and IL‐27 enhance human β‐defensin‐2 production in human keratinocytes

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IL‐18 enhances IFN‐γ‐induced production of CXCL9, CXCL10, and CXCL11 in human keratinocytes

Cited by 154 publications

References 52 publications

Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8 + T-cell axis

Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8 + T-cell axis

Chemokines and Chemokine Receptors in Neurological Disease: Raise, Retain, or Reduce?

IL‐12, IL‐23, and IL‐27 enhance human β‐defensin‐2 production in human keratinocytes

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Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8 ⁺ T-cell axis

Toll-like receptor-5 agonist, entolimod, suppresses metastasis and induces immunity by stimulating an NK-dendritic-CD8 ⁺ T-cell axis