The Function of Fish Cytokines

Zou, Jun; Secombes, Christopher J.

doi:10.3390/biology5020023

Cited by 398 publications

(258 citation statements)

References 278 publications

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“…In our model, upregulation of proinflammatory mediators progression to an immunosuppressed phenotype, often implicated as a cause of later secondary infections in sepsis (41). The cytokines and chemokines measured in this study are commonly used as measures of the teleost immune response and have been previously shown to be fairly conserved (sequence conservation and/or structural conservation) between zebrafish and mammals (16,42,43). However, many of the zebrafish cytokine genes have duplicated and diverged independently over the course of evolution, the functional implications of which associated with human sepsis.…”

Section: Discussionmentioning

confidence: 98%

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

Philip

Wang

Mauro

et al. 2017

Mol Med

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Sepsis is a leading cause of death worldwide. Current treatment modalities remain largely supportive. Intervention strategies focused on inhibiting specific mediators of the inflammatory host response have been largely unsuccessful, a consequence of an inadequate understanding of the complexity and heterogeneity of the innate immune response. Moreover, the conventional drug-development pipeline is time-consuming and expensive, and the low success rates associated with cell-based screens underline the need for whole-organism screening strategies, especially for complex pathological processes. Here, we established a lipopolysaccharide (LPS)-induced zebrafish endotoxemia model, which exhibits the major hallmarks of human sepsis, including edema and tissue/organ damage, increased vascular permeability and vascular leakage accompanied by altered expression of cellular junction proteins, increased cytokine expression, immune cell activation and reactive oxygen species (ROS) production, reduced circulation and increased platelet aggregation. We tested the suitability of the model for phenotype-based drug screening using three primary readouts: mortality, vascular leakage and ROS production. Preliminary screening identified fasudil, a drug known to protect against vascular leakage in murine models, as a lead hit, thereby validating the utility of our model for sepsis drug screens. This zebrafish sepsis model has the potential to rapidly analyze sepsis-associated pathologies and cellular processes in the whole organism, as well as to screen and validate many compounds that can modify sepsis pathology in vivo.

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Section: Discussionmentioning

confidence: 98%

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

Philip

Wang

Mauro

et al. 2017

Mol Med

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“…Type II IFNs are also present in fish [1], but they will not be discussed in this review. Following the discovery of the induction of type I IFNs activity by influenza virus [2], human IFNα and -β genes have been cloned [3,4], and an impressive diversity of type I IFN genes was discovered.…”

Section: Introductionmentioning

confidence: 99%

The Peculiar Characteristics of Fish Type I Interferons

Boudinot

Langevin

Secombes

et al. 2016

Viruses

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Antiviral type I interferons (IFNs) have been discovered in fish. Genomic studies revealed their considerable number in many species; some genes encode secreted and non-secreted isoforms. Based on cysteine motifs, fish type I IFNs fall in two subgroups, which use two different receptors. Mammalian type I IFN genes are intronless while type III have introns; in fish, all have introns, but structurally, both subgroups belong to type I. Type I IFNs likely appeared early in vertebrates as intron containing genes, and evolved in parallel in tetrapods and fishes. The diversity of their repertoires in fish and mammals is likely a convergent feature, selected as a response to the variety of viral strategies. Several alternative nomenclatures have been established for different taxonomic fish groups, calling for a unified system. The specific functions of each type I gene remains poorly understood, as well as their interactions in antiviral responses. However, distinct induction pathways, kinetics of response, and tissue specificity indicate that fish type I likely are highly specialized, especially in groups where they are numerous such as salmonids or cyprinids. Unravelling their functional integration constitutes the next challenge to understand how these cytokines evolved to orchestrate antiviral innate immunity in vertebrates.

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“…It is well known in both mammals and fish that IFNs are essential for inducing an antiviral state within the cells (Zou & Secombes , ; Castro & Tafalla ), but less is known about the production of proinflammatory cytokines upon viral infections in fish. Therefore, in addition to measure the transcriptional level of IFNs (IFNa‐d), we measured the production of the cytokines TNF‐α1, TNF‐α2, IL‐1β, IL‐6 and IL‐12 p40.…”

Section: Discussionmentioning

confidence: 99%

“…Proinflammatory cytokines are produced after activation of the NF‐κβ signalling pathway, which is downstream of ligand binding to TLR, RLR, NLR or CLR. IL‐1β is produced by range of cell types after activation of PRRs by PAMPs or danger‐associated molecular patterns (DAMPs) (Zou & Secombes and references therein), and it regulates the inflammatory process in fish as in mammals. A study from trout showed that when IL‐1β was administered intraperitoneally, both the number of phagocytes that migrated into the peritoneal cavity and the phagocytic and lysosomal activity of the macrophages increased (Hong et al .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Molecular cloning of MDA5, phylogenetic analysis of RIG‐I‐like receptors (RLRs) and differential gene expression of RLRs, interferons and proinflammatory cytokines after in vitro challenge with IPNV, ISAV and SAV in the salmonid cell line TO

Nerbøvik

Solheim

Eggestøl

et al. 2017

Journal of Fish Diseases

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The RIG-I receptors RIG-I, MDA5 and LGP2 are involved in viral recognition, and they have different ligand specificity and recognize different viruses. Activation of RIG-I-like receptors (RLRs) leads to production of cytokines essential for antiviral immunity. In fish, most research has focused on interferons, and less is known about the production of proinflammatory cytokines during viral infections. In this study, we have cloned the full-length MDA5 sequence in Atlantic salmon, and compared it with RIG-I and LGP2. Further, the salmonid cell line TO was infected with three fish pathogenic viruses, infectious pancreatic necrosis virus (IPNV), infectious salmon anaemia virus (ISAV) and salmonid alphavirus (SAV), and differential gene expression (DEG) analyses of RLRs, interferons (IFNa-d) and proinflammatory cytokines (TNF-α1, TNF-α2, IL-1β, IL-6, IL-12 p40s) were performed. The DEG analyses showed that the responses of proinflammatory cytokines in TO cells infected with IPNV and ISAV were profoundly different from SAV-infected cells. In the two aforementioned, TNF-α1 and TNF-α2 were highly upregulated, while in SAV-infected cells these cytokines were downregulated. Knowledge of virus recognition by the host and the immune responses during infection may help elucidate why and how some viruses can escape the immune system. Such knowledge is useful for the development of immune prophylactic measures.

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The Function of Fish Cytokines

Cited by 398 publications

References 278 publications

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

Development of a Zebrafish Sepsis Model for High-Throughput Drug Discovery

The Peculiar Characteristics of Fish Type I Interferons

Molecular cloning of MDA5, phylogenetic analysis of RIG‐I‐like receptors (RLRs) and differential gene expression of RLRs, interferons and proinflammatory cytokines after in vitro challenge with IPNV, ISAV and SAV in the salmonid cell line TO

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