Noradrenaline And Adrenergic Signaling

8.1. Apoptosis and the invertebrate neuroimmune response

Apoptosis contributes to maintenance and preservation of a balanced immune system in vertebrates. With the exception of mollusks, information is scarce concerning apoptotic processes and regulation of immunity in other invertebrates. NA a catecholamine produced by the neuroendo-crineimmune system induces apoptosis in oyster hemocytes. The apoptosis-inducing effect of NA can be mimicked by isoproterenol and blocked by propranolol, indicating that NA triggers apoptosis via a a-adrenergic signaling pathway. Exposure to the pan-caspase inhibitor Z-VAD-FMK or expression of the caspase inhibitor P35 under the transcriptional control of a mollusk heat shock protein 70 (hsp70) gene promoter reduces levels of apoptotic cells in hemocytes treated with isoproterenol. P35-sensitive caspases are probably involved in apoptosis and are triggered by a-adrenergic signaling. Moreover, mitogen-activated protein kinases and Rho, a member of the Ras GTPase family, may be involved in anti-apoptotic mechanisms that modulate the apoptotic effect of NA [58]

8.2. Heat shock proteins and neuroimmune responses

Expression of heat shock proteins is a homeostatic mechanism induced in prokaryotic and eukaryotic cells in response to metabolic and environmental insults. Increasing evidence suggests that in mammals, the hsp response is integrated with physiological responses through neuroendocrine signaling. Oyster and abalone hemocytes were transfected with a gene construct containing a gastropod hsp70 gene promoter linked to the luciferase reporter-gene. NA and a-adrenergic stimulations induced the expression of luciferase in these transfected mollusk immunocytes. Exposure of hemocytes to NA or to the oc-adrenoceptor agonist phenylephrine (PE) causes expression of the inducible isoform of the hsp70 protein determined through immu-noblotting. Pertussis toxin, the phospholipase C (PLC) inhibitor U73122, the protein kinase C (PKC) inhibitor calphostin C, the Ca++-dependent PKC inhibitor Go 6976 and the phosphati-dylinositol 3-kinase (PI 3-kinase) inhibitor LY294002 blocked the PE-mediated induction of the hsp70 gene promoter. Thus, a-adrenergic signaling induces transcriptional upregulation of hsp70 in molluscan hemocytes through a PTX-sensitive G-protein, PLC, Ca++-dependent PKC and PI 3-kinase. Neuroendocrine signaling and the hsp70 response share an apparent link in molluscan immune cells [59].

8.3. Catecholamines and neuroimmune regulation

Catecholamines regulate several physiological processes in mollusks. The p-adrenoceptor agonist isoproterenol mimics the inhibitory effects of NA on phagocytosis by oyster hemocytes, whereas the a-adrenoceptor agonist phenylephrine had no significant effect. The p-adrenocep-tor antagonist propanolol, but not the a-adrenoceptor antagonist prazosin, prevented inhibition of phagocytosis by NA. The type IV phosphodiesterase inhibitor rolipram acted synergistically with a suboptimal concentration of isoproterenol to inhibit phagocytosis, and the protein kinase A inhibitor H-89, but not the protein kinase C inhibitor calphostin C, attenuated the effect of isoproterenol. NA modulates phagocytosis via a p-adrenergic receptor/cAMP/protein kinase A signaling pathway [60]. Catecholamines are present in the microenvironment of immunocytes. NA the principal CA circulating in bivalve hemolymph exerts a dose-dependent inhibitory effect on luminol-dependent chemiluminescence- (CL)-responses in oyster hemocytes. The a-adrenoceptor agonist phenylephrine exerts no significant effect whereas the P-adrenoceptor agonist isoproterenol mimicked the inhibitory effects of NA on the CL-response. The P-adrenoceptor antagonist propanolol, but not the a-adrenoceptor antagonist prazosin, prevents the negative effects of NA on the CL-response. P-adrenergic receptors are probably present on hemocyte surfaces thus allowing NA to down-regulate the CL-response [61]

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