Group IIA secretory phospholipase A2 stimulates inducible nitric oxide synthase expression via ERK and NF-κB in macrophages

Baek, Suk‐Hwan; Lim, Jun-Hee; Park, Dae‐Won; Kim, Seong-Yong; Lee, Young Han; Kim, Jae‐Ryong; Kim, Jung-Hye

doi:10.1002/1521-4141(200109)31:9<2709::aid-immu2709>3.0.co;2-3

Cited by 27 publications

(20 citation statements)

References 36 publications

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“…The lack of specific Abs or ligands for these receptors in human cells currently precludes their characterization on eosinophils. However, we provide evidence that both group IA and IIA sPLA 2 s induce activation of ERK1/2, a signaling pathway that has been coupled to activation of the M-type receptor in other cell types (19,39). These data support the hypothesis that sPLA 2 s may activate human eosinophils by interacting with the M-type receptor.…”

Section: Discussionsupporting

confidence: 73%

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Secretory Phospholipases A2 Activate Selective Functions in Human Eosinophils

Triggiani

Granata

Balestrieri

et al. 2003

The Journal of Immunology

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Secretory phospholipases A2 (sPLA2s) are released in large amounts in the blood of patients with systemic inflammatory diseases and accumulate at sites of chronic inflammation, such as the airways of patients with bronchial asthma. Blood eosinophils or eosinophils recruited in inflammatory areas therefore can be exposed in vivo to high concentrations of sPLA2. We have examined the effects of two structurally different sPLA2s (group IA and group IIA) on several functions of eosinophils isolated from normal donors and patients with hypereosinophilia. Both group IA and IIA sPLA2 induced a concentration-dependent release of β-glucuronidase, IL-6, and IL-8. Release of the two cytokines was associated with the accumulation of their specific mRNA. In addition, sPLA2s induced the surface expression of CD44 and CD69, two major activation markers of eosinophils. In contrast, none of the sPLA2s examined induced the production of IL-5, the de novo synthesis of leukotriene C4 and platelet-activating factor, or the generation of superoxide anion from human eosinophils. Incubation of eosinophils with the major enzymatic products of the sPLA2s (arachidonic acid, lysophosphatidylcholine, or lysophosphatidic acid) did not reproduce any of the enzymes’ effects. In addition, inactivation of sPLA2 enzymatic activity by bromophenacyl bromide did not influence the release of β-glucuronidase or of cytokines. Stimulation of eosinophils by sPLA2s was associated with activation of extracellular signal-regulated kinases 1/2. These results indicate that sPLA2s selectively activate certain proinflammatory and immunoregulatory functions of human eosinophils through mechanism(s) independent from enzymatic activity and from the generation of arachidonic acid.

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Section: Discussionsupporting

confidence: 73%

“…Binding of sPLA 2 s to the M-type receptor expressed on mast cells and macrophages has been shown to activate intracellular signaling through the ERK1/2 pathway (19,39). To verify this mechanism in human eosinophils, cells were stimulated with group IA sPLA 2 (10 g/ml).…”

Section: Activation Of Erk1/2 By Spla 2 In Human Eosinophilsmentioning

confidence: 99%

Secretory Phospholipases A2 Activate Selective Functions in Human Eosinophils

Triggiani

Granata

Balestrieri

et al. 2003

The Journal of Immunology

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“…On the other hand, treatment with either drug diminished the RV-induced phosphorylation of ERK1/2 (lanes 7 to 10). In the presence of 20 mM NH 4 Cl or 250 nM BA1, only low, but detectable, levels of p-ERK1/2 were observed in the RV-stimulated cells (lanes 8 and 10). The decreased level of ERK1/2 phosphorylation was not due to the degradation of total ERK1/2, as the protein levels of ERK1/2 in each sample were comparable (lanes 6 to 10).…”

Section: Rv Virions Trigger Erk1/2 Activation In Macrophagesmentioning

confidence: 97%

“…To further characterize the RVinduced activation of cellular signaling, we assessed the effects of MEK inhibitors on the phosphorylation of ERK1/2 in RV- 4 Cl and BA1 or untreated (Ϫ), were stimulated with either LPS (50 ng/ml) or CVS virions (10 FFU/ml) for 2 h. After additional incubation in the absence or presence of inhibitors, the cells were subjected to Western blot analyses of p-ERK1/2, total ERK1/2, and ␣-tubulin as described in the text. The data are from one of three individual experiments.…”

Section: Rv Virions Trigger Erk1/2 Activation In Macrophagesmentioning

confidence: 99%

Rabies Virus Stimulates Nitric Oxide Production and CXC Chemokine Ligand 10 Expression in Macrophages through Activation of Extracellular Signal-Regulated Kinases 1 and 2

Nakamichi¹,

Inoue

Takasaki³

et al. 2004

J Virol

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Macrophages represent an essential part of innate immunity, and the viral infection of macrophages results in the release of multiple proinflammatory mediators, such as nitric oxide (NO), cytokines, and chemokines. This study was undertaken to define the molecular mechanism of macrophage activation in response to rabies virus (RV) infection. In RAW264 murine macrophage cells, a well-characterized macrophage model, RV replication was strictly restricted, whereas cell proliferation was significantly enhanced upon RV inoculation. Transcriptional analyses for the expression of inducible forms of NO synthase (iNOS), cytokines, and chemokines revealed that RV virions potentiate the gene expression of iNOS and CXC chemokine ligand 10 (CXCL10), a major chemoattractant of T helper cell type 1. However, RV stimulation had little or no effect on the expression profiles of proinflammatory cytokines and other types of chemokines. In macrophages stimulated with UV-inactivated RV virions, as well as infectious viruses, the phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2, members of the mitogen-activated protein kinase family, was significantly induced. Specific inhibitors of MAPK/ERK kinase reduced the RV-induced production of NO and CXCL10. Furthermore, the RV-induced activation of the ERK1/2 pathway was severely impaired by the neutralization of the endosomal and lysosomal pH environment with lysosomotropic agents, indicating that endocytosis is a key step leading to the activation of ERK1/2 signaling. Taken together, these results suggest that the ERK1/2-mediated signaling pathway plays a cardinal role in the selective activation of macrophages in response to RV virions, thereby regulating cellular functions during virus infection.Rabies virus (RV) is a negative-strand RNA virus belonging to the Rhabdoviridae family, genus Lyssavirus. Most RV strains are highly neurotropic, which usually causes a fatal infection in warm-blooded animals, and viral replication primarily occurs in neurons as a cellular target (43). It has been reported that RV replicates in muscle cells prior to the invasion of the peripheral nervous system and central nervous system (CNS) in vivo (62). In vitro, it is known that a highly neurovirulent RV strain, challenge virus standard (CVS), and an attenuated strain, high egg passage (HEP)-Flury (hereafter called HEP), infect a variety of cell types, including nonneuronal cells (26,82,84,85).It is well known that infection of experimental animals with nonpathogenic RV strains triggers a strong antiviral immune response (90). Recent studies have demonstrated that the strong antiviral immune response elicited by attenuated RV infection is closely related to the induction of apoptosis in infected cells due to the expression of viral glycoprotein (61,76). Several groups have attempted to develop vaccine vehicles using RV-based vectors. It has been reported that the RV vectors expressing foreign antigens induce strong humoral and cellular responses against other kinds of viral pathogens, s...

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“…Clearly this does not exclude the potential implication of an indirect effect via modifications of the immune system per se, particularly through the interaction with a receptor on certain cell types (40). Several studies with various sPLA 2 s, including human group IIA, have shown that these sPLA 2 s can trigger iNOS induction (41), COX-2 induction (42) and IL-6, IL-8, and TNF-␣ cytokine secretion (43), through a mechanism involving ERK1/2 (41,44). However, in our study, sPLA 2 -IIA was found effective even against infection with a B. anthracis strain secreting the toxins that are known to block the MAPK cascade (ERK/P38) through MEK cleavage (45,46); this observation suggests a predominant direct bactericidal effect.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Protective Role of Human Group IIA Phospholipase A2 against Experimental Anthrax

Piris-Giménez

Payá

Lambeau

et al. 2005

The Journal of Immunology

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Anthrax is an acute disease caused by Bacillus anthracis. Some animal species are relatively resistant to anthrax infection. This trait has been correlated to the extent of the local inflammatory reaction, suggesting innate immunity to be the first line of defense against B. anthracis infection in nonimmunized hosts. Group IIA secreted phospholipase A2 (sPLA2-IIA) is produced in particular by macrophages and possesses potent antibacterial activity especially against Gram-positive bacteria. We have previously shown in vitro that sPLA2-IIA kills both germinated B. anthracis spores and encapsulated bacilli. Here we show that sPLA2-IIA plays in vivo a protective role against experimental anthrax. Transgenic mice expressing human sPLA2-IIA are resistant to B. anthracis infection. In addition, in vivo administration of recombinant human sPLA2-IIA protects mice against B. anthracis infection. The protective effect was observed both with a highly virulent encapsulated nontoxinogenic strain and a wild-type encapsulated toxinogenic strain, showing that toxemia did not hinder the sPLA2-IIA-afforded protection. sPLA2-IIA, a natural component of the immune system, may thus be considered a novel therapeutic agent to be used in adjunct with current therapy for treating anthrax. Its anthracidal activity would be effective even against strains resistant to multiple antibiotics.

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Group IIA secretory phospholipase A2 stimulates inducible nitric oxide synthase expression via ERK and NF-κB in macrophages

Cited by 27 publications

References 36 publications

Secretory Phospholipases A2 Activate Selective Functions in Human Eosinophils

Secretory Phospholipases A2 Activate Selective Functions in Human Eosinophils

Rabies Virus Stimulates Nitric Oxide Production and CXC Chemokine Ligand 10 Expression in Macrophages through Activation of Extracellular Signal-Regulated Kinases 1 and 2

In Vivo Protective Role of Human Group IIA Phospholipase A2 against Experimental Anthrax

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