Bv8, the amphibian homologue of the mammalian prokineticins, induces a proinflammatory phenotype of mouse macrophages

Abstract

1 The small protein Bv8, isolated from the amphibian skin, belongs to a novel family of secreted proteins linked to several biological effects. We describe the expression of Bv8/prokineticins and their receptors in mouse macrophages, and characterize their proinflammatory activities. 2 The rodent analogue of Bv8, prokineticin-2, is expressed by macrophages, as well as its G-proteincoupled receptor prokineticin receptor (PKR-1 and PKR-2). PKR-1 is expressed more abundantly. 3 Bv8 induces potent chemotaxis of macrophages at concentrations as low as 10 À12 M. 4 It stimulates lipopolysaccharide-induced production of the proinflammatory cytokines IL-1 and IL-12, reducing that of the anti-inflammatory cytokine IL-10. The effects are observed starting at the very low concentration of 10 À11 M. 5 Effects on chemotaxis and cytokine are not pertussis-toxin sensitive, but are completely prevented by addition of the phospholipase inhibitor U73122, suggesting a G q protein is involved in the Bv8-induced effects. 6 Studies in PKR-1 knockout mice indicate that all the activities exerted by Bv8 on macrophages are mediated by the PKR-1 receptor. 7 In conclusion, Bv8 appears to be able to induce the macrophage to migrate and to acquire a proinflammatory phenotype.

Prokineticins are neuroprotective in models of cerebral ischemia and ischemic tolerance in vitro

“…In cardiac tissue, Bv8 was able to attenuate cardiomyocyte oxidative stress (Urayama et al, 2008) and, in a very recent report, a novel PKR1 agonist was demonstrated to prevent myocardial infarction in mice via an angiogenic mechanism (Gasser et al, 2015). However, reports also exist showing that Bv8/PK2 prokineticins induce a proinflammatory phenotype in mouse macrophages (Martucci et al, 2006), exacerbate the infarct volume in rats subjected to transient or permanent cerebral focal ischemia (Cheng et al, 2012), or reduce cell viability in primary rat cortical cultures (Severini et al, 2015). In these latter studies, prokineticin receptor blockers were able to protect against post-ischemic cell death (Cheng et al, 2012) or amyloid beta-induced neurotoxicity (Severini et al, 2015).…”

“…Other mechanisms are also possible: for example, the hyperalgesic effects of very low (femtomolar) concentrations of Bv8 are at least partly mediated by activation of the TRPV1 receptor , which has been shown to produce toxic effects and exacerbate OGD injury in our organotypic hippocampal slices (Landucci et al, 2011). Because of the absence of a vascular system and inflammatory cells in cortical cell or hippocampal slice cultures, other possible mechanisms known to be triggered by prokineticins, such as the pro-inflammatory (Martucci et al, 2006;Cheng et al, 2012) or angiogenic (LeCouter and Ferrara, 2003;Monnier and Samson, 2010) effects, can be ruled out in our experimental models.…”

“…These two peptides are highly conserved across species (LeCouter et al, 2004;Giannini et al, 2009) and activate two highly homologous receptors, prokineticin receptor 1 (PKR1) and PKR2 (Negri and Lattanzi, 2011), which are coupled to a variety of G proteins and hence to intracellular Ca 2þ mobilization and activation of the ERK1/2 and Akt pathways (Lin et al, 2002;Masuda et al, 2002;Soga et al, 2002). Prokineticins (especially PK2) and their receptors are largely expressed in CNS (Cheng et al, 2006) and regulate multiple biological functions in the CNS including hyperalgesia (Mollay et al, 1999), neurogenesis in the olfactory bulb (Ng et al, 2005), neuronal survival (Melchiorri et al, 2001) and inflammation (Martucci et al, 2006). Recent studies have implicated PK2 in human diseases such as, for example, Kallmann syndrome, which can be determined by loss-offunction mutations in the gene encoding for PK2 (Pitteloud et al, 2007) or CNS autoimmune demyelination, in which PK2 has been identified as a critical immune regulator (Abou-Hamdan et al, 2015).…”

“…Bv8 has been shown to protect against NMDA excitotoxicity in cerebellar granule cell cultures (Melchiorri et al, 2001), to protect cardiomyocytes against oxidative stress (Urayama et al, 2008), and to promote neurogenesis in the olfactory bulb (Ng et al, 2005). On the other hand, PK2 induces a proinflammatory phenotype in mouse macrophages (Martucci et al, 2006) and worsens the infarct volume, central inflammation and the behavioural outcome in models of stroke in vivo (Cheng et al, 2012).…”

The chemokine Bv8/prokineticin 2 is up-regulated in inflammatory granulocytes and modulates inflammatory pain

“…Activation of PKRs in primary afferent C fibers sensitizes nociceptors to thermal, mechanical, and chemical stimuli (14)(15)(16). In neutrophils, macrophages, and dendritic cells it promotes chemotaxis and cytokine release (17)(18)(19)(20), and in capillary endothelial cells it stimulates angiogenesis (21). Testis, peripheral blood leukocytes, and macrophages express two mRNA transcripts of PK2, one coding for the canonical PK2 and the other for an elongated form containing additional 21 basic amino acids between Lys-47 and Val-48 of the mature PK2 protein, named PK2L (6,19,22).…”