Evolution of the Inflammatory Response in Vertebrates: Fish TNF-α Is a Powerful Activator of Endothelial Cells but Hardly Activates Phagocytes

Abstract

TNF-α is conserved in all vertebrate classes and has been identified in all taxonomic groups of teleost fish. However, its biological activities and its role in infection are largely unknown. Using two complementary fish models, gilthead seabream and zebrafish, we report here that the main proinflammatory effects of fish TNF-α are mediated through the activation of endothelial cells. Thus, TNF-α promotes the expression of E-selectin and different CC and CXC chemokines in endothelial cells, thus explaining the recruitment and activation of phagocytes observed in vivo in both species. We also found that TLR ligands, and to some extent TNF-α, were able to increase the expression of MHC class II and CD83 in endothelial cells, which might suggest a role for fish endothelial cells and TNF-α in Ag presentation. Lastly, we found that TNF-α increases the susceptibility of the zebrafish to viral (spring viremia of carp virus) and bacterial (Streptococcus iniae) infections. Although the powerful actions of fish TNF-α on endothelial cells suggest that it might facilitate pathogen dissemination, it was found that TNF-α increased antiviral genes and, more importantly, had little effect on the viral load in early infection. In addition, the stimulation of ZF4 cells with TNF-α resulted in increased viral replication. Together, these results indicate that fish TNF-α displays different sorts of bioactivity to their mammalian counterparts and point to the complexity of the evolution that has taken place in the regulation of innate immunity by cytokines.

MAVS splicing variants contribute to the induction of interferon and interferon-stimulated genes mediated by RIG-I-like receptors

“…However, our previous custom PCR arrays (SABiosciences, QIAGEN company) showed that IFN2 could be detected in zebrafish embryos (Hu et al, 2014). In the present study, IFN2 expression in zebrafish embryos was examined by using the same primers from others (López-Muñoz et al, 2009;Roca et al, 2008), but different from the IFN2 primers used by Aggad et al (2009), which gave similar results to PCR arrays. From these experiments, it thus seems that all four IFNs are constitutively expressed in zebrafish embryos.…”

A chemical enterocolitis model in zebrafish larvae that is dependent on microbiota and responsive to pharmacological agents

“…**P < 0.01, ***P < 0.001. antibody method (Fleming et al, 2010). Because of the substantial difference in the biological role of TNF-a in mammals and zebrafish, we examined the transcription of a panel of pro-inflammatory cytokines as a more accurate measure of inflammation (Roca et al, 2008). Consistent with previous studies of zebrafish larval intestinal infection, an early induction of pro-inflammatory cytokine transcription has been observed in this model (Oehlers et al, 2010).…”

Receptor-Mediated and Lectin-Like Activities of Carp (Cyprinus carpio) TNF-α

“…Another study in zebrafish (77), however, did show a role for TNF-␣ signaling in neutrophil influx into the intestine in response to proinflammatory stimuli induced by LPS. Most recently, a study in seabream (27) showed that endothelial cells, more than phagocytes, might be the primary target of fish TNF-␣, suggesting that TNF-␣ is primarily involved in the recruitment of phagocytes to inflammatory sites rather than in the direct activation of phagocytes.…”

“…The conservation of the lectin-like activity of TNF-␣ among different fish species is opposed to the differences between fish species with regard to the receptor-dependent proinflammatory functions of TNF-␣ (24,25,22,27), most of which have been studied in vitro. The role played by fish TNF-␣ during immune responses in vivo is largely unknown owing to the lack of suitable knockout or transgenic animal models.…”

“…For example, both in rainbow trout (Oncorhynchus mykiss) (24) and goldfish (Carassius auratus) (22), TNF-␣ stimulates phagocyte activity in vitro, albeit at different concentrations. In contrast, seabream (Sparus aurata) TNF-␣ is a potent activator of endothelial cells but does not activate phagocytes directly (27). Instead, supernatant from seabream endothelial cells treated with TNF-␣ promoted the adhesion, migration, and activation of leukocytes.…”