Macrophage migration inhibitory factor induces MMP-9 expression in macrophages via the MEK-ERK MAP kinase pathway.

We have shown previously that macrophage migration inhibitory factor (MIF) may play a role in the destabilization of atherosclerotic plaques by activating matrix metalloproteinase protein-9 (MMP-9). The aim of this study is to investigate the signaling mechanism by which MIF induces MMP-9 expression and activation in a murine macrophage line (RAW264.7). MIF was able to activate extracellular signal-regulated kinase 1/2 (ERK1/2), to a less extent JNK, but not p38 mitogen-activated protein (MAP), MAP kinase to induce MMP9 mRNA and protein expression in RAW264.7 murine macrophages. This was confirmed by the findings that addition of an ERK MAP kinase inhibitor (PD98059) but not a p38 inhibitor (SB203589) abolished MIF-induced MMP-9 expression and activation, whereas addition of a JNK inhibitor (SP600125) produced a partially inhibitory effect. The functional role of mitogen-activated protein kinase kinase (MEK)-ERK MAP kinase in MIF-induced MMP-9 expression was further confirmed by overexpressing dominant negative MEK (DN-MEK) and DN-ERK MAP kinases. Interestingly, constitutive expression of a wild-type (WT)-MEK alone was also capable of inducing a low, but significant MMP-9 mRNA and protein expression but did not cause a further increase in MMP-9 in response to MIF. MIF activates the MEK-ERK MAP kinase pathway to induce MMP-9 expression by murine macrophages. Activation of this pathway is necessary for MMP-9 expression and activation in response to MIF stimulation.     

The neutrophil-activating protein of Helicobacter pylori (HP-NAP) activates the MAPK pathway in human neutrophils

Infection by Helicobacter pylori causes an acute inflammatory response followed by a chronic infection of the human gastric mucosa characterized by the infiltration of neutrophils andmononuclear inflammatory cells. The neutrophil-activating protein of Helicobacter pylori (HP-NAP) is a virulence factor that activates neutrophils, monocytes, and mast cells. However, the mechanism by which HP-NAP activates these cells is not fully understood. Here, we show that HP-NAP induces extracellular regulated kinase (ERK) and p38-mitogen-activated protein kinase (MAPK) activation in human neutrophils; c-Jun N-terminal kinase is not activated by HP-NAP. A MAPK/ERK kinase inhibitor and a p38-MAPK inhibitor suppress HP-NAP-mediated neutrophil oxidative burst, adhesion, andchemotaxis, but not actin polymerization. Pertussis toxin (PTX) inhibits all these neutrophil functions and the MAPK activation caused by HP-NAP. These results demonstrate that HP-NAP activates neutrophils through a PTX-sensitive pathway and that ERK and p38-MAPK are involved in many neutrophil functions stimulated by HP-NAP.     

Activation of the p38 MAP kinase pathway is required for foam cell formation from macrophages exposed to oxidized LDL

Endocytosis of oxidized low density lipoproteins (oxLDL) by macrophages, mediated by scavenger receptors, is thought to play a central role in foam cell formation and, thus, in the pathogenesis of atherosclerosis. OxLDL activates several MAP kinases, including the ERK, JNK and p38 MAP kinases, but the role of these activations in oxLDL uptake has not been studied. In the present investigation, we find that SB203580, a specific inhibitor of p38, blocks oxLDL-exposed J774 cells from becoming foam cells. Inhibition of foam cell formation by blockade of the p38 pathway is, at least in part, due to inhibition of oxLDL-induced up-regulation of the scavenger receptor CD36. Using pharmaceutical inhibitors and dominant active MAP kinase kinases, we demonstrated that activation of the p38 pathway, but not the ERK or JNK pathways, is necessary and sufficient to transactivate PPARgamma, a nuclear receptor that has recently been shown to play a pivotal role in oxLDL-induced CD36 expression. Our results for the first time demonstrate a regulation of CD36 by p38, and the importance of the p38 pathway in regulation of foam cell formation.     

Implication of mitogen-activated protein kinases in T84 cell responses to enteropathogenic Escherichia coli infection

Enteropathogenic Escherichia coli (EPEC) infection of T84 cells induces a decrease in transepithelial resistance, the formation of attaching and effacing (A/E) lesions, and cytokine production. The purpose of this study was to investigate the ability of EPEC to activate mitogen-activated protein (MAP) kinases in T84 cells and to correlate these signaling pathways with EPEC-induced cell responses. T84 cells were infected with either the wild-type (WT) EPEC strain E2348/69 or two mutants, intimin deletion strain CVD206 (deltaeaeA) and type III secretion apparatus mutant strain CVD452 (deltaescN::aphA). Infection of T84 cells with WT but not mutant EPEC strains induced tyrosine phosphorylation of several proteins in T84 cells, including the p46 and p52 Shc isoforms. Kinetics studies revealed that ERK1/2, p38, and c-Jun N-terminal kinase (JNK) MAP kinases were activated in cells infected with strain E2348/69 but not with the mutant strains. Inhibition of MAP kinases with PD98059 or SB203580 did not affect the EPEC-induced decrease in transepithelial resistance or actin accumulation beneath the WT bacteria, but these two inhibitors significantly decreased interleukin-8 (IL-8) synthesis. We demonstrate that EPEC induces activation of ERK1/2, p38, and JNK cascades, which all depend on bacterial adhesion and expression of the bacterial type III secretion system. ERK1/2 and p38 MAP kinases were equally implicated in IL-8 expression but did not participate in A/E lesion formation or transepithelial resistance modification, indicating that the signaling pathways involved in these events are distinct.     

Differential activation and regulation of mitogen-activated protein kinases through the antigen receptor and CD40 in human B cells.

In human B cells, antigen receptor ligation and CD40 ligation are known to activate the extracellular-regulated kinases (ERK) and c-Jun N-terminal kinase (JNK) pathways, which in turn regulate many important B cell functions. We previously reported that antigen receptor ligation activated the ERK pathway whereas CD40 ligation activated the JNK/stress-activated protein kinase (SAPK) pathway. Here, we demonstrate that another SAPK, p38/Hog1, is activated by both antigen receptor ligation or CD40 ligation in a human B-lymphoblastoid cell line and tonsillar B cells. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase, partially inhibited ERK2 and p38 activation triggered through the B cell receptor whereas activation of JNK1 and p38 through CD40 was not affected. PD98059, a specific inhibitor of mitogen-activated extracellular response kinase kinase (MEK), significantly inhibited ERK2 activation and partially inhibited p38 activation triggered by anti-IgM antibody treatment, but did not affect CD40-dependent signaling events. In addition, anti-IgM antibody-induced signaling pathways were shown to be PKC-dependent in contrast to the CD40-induced signaling pathways. Thus, the B cell receptor and CD40 recruit the ERK, JNK and p38 pathways by using different upstream effectors.     

Differential activation of mitogen-activated protein kinase signalling pathways in the hippocampus of CRND8 transgenic mouse, a model of Alzheimer's disease

Transgenic Centre for Research in Neurodegenerative Diseases 8 (TgCRND8) mice expressing a double mutant form of human amyloid precursor protein represent a good model of Alzheimer's disease, and can be useful to clarify the involvement of mitogen-activated protein kinases (MAPK) dysregulation in the pathophysiology of this neurodegenerative disorder. Activation of extracellular regulated kinase (ERK) 1/2, jun kinase (JNK) and p38MAPK was studied in the hippocampus of 7-month-old TgCRND8 mice by immunohistochemistry and Western blot analysis using antibodies selective for the phosphorylated, and thus active, forms of the enzymes. We demonstrated that the three main MAPK pathways were differentially activated in cells of the hippocampus of TgCRND8 mice in comparison to wild type (Wt) littermates, p38MAPK and JNK being more activated, while ERK less activated. p38MAPK was significantly activated in microglia, astrocytes and neurons, around and distant from the plaques. JNK was highly activated in cells closely surrounding the plaques. No difference was observed in the activation of the two major bands of JNK, at a molecular weight of 46 kDa and 54 kDa. These data indicate the possible involvement of p38MAPK and JNK pathways dysregulation in the pathogenesis of Alzheimer's disease. The ERK2 isoform of the ERK pathway was less activated in the hippocampal dentate gyrus of Tg mice in basal conditions. Furthermore activation of the ERK pathway by ex vivo cholinergic stimulation with carbachol caused significantly higher activation of ERK in the hippocampus of Wt mice than in Tg mice. These findings may pose a molecular basis for the memory disruption of Alzheimer's disease, since proper functioning of the basal forebrain cholinergic neurons and of ERK2 is critical for memory formation.     

Leishmania lipophosphoglycan activates the transcription factor activating protein 1 in J774A.1 macrophages through the extracellular signal-related kinase (ERK) and p38 mitogen-activated protein kinase

Leishmania donovani is an obligatory intracellular pathogen that resides and multiplies in the phagolysosomes of macrophages. The outcome of this infection depends on the balance between the host ability to activate macrophage killing and the parasite ability to suppress or evade this host immune response. Lipophosphoglycan (LPG) glycoconjugate, the surface molecule of the protozoan parasite is a virulence determinant and a major parasite molecule involved in this process. In this study, we examined the ability of Leishmania and its surface molecule, lipophosphoglycan to activate activating protein 1 (AP-1) through the mitogen-activated protein kinase (MAPK) cascade. We report here that the Leishmania surface molecule, lipophosphoglycan stimulates the simultaneous activation of all three classes of MAP kinases, extracellular signal-related kinases (ERKs), the c-jun amino-terminal kinase (JNK) and the p38 MAP kinase with differential kinetics in J774A.1 macrophage cell line. Furthermore, both L. donovani and its surface molecule lipophosphoglycan resulted in a dose- and time-dependent induction of AP-1 DNA-binding activity. We have also shown a dose-dependent increase of AP-1 binding activity in both low and high virulent strains of parasite. The use of inhibitors selective for ERK (PD98059) and p38 (SB203580) pathway showed that pre-incubation of cells with either SB203580 or PD98059 affected the binding activity of AP-1 suggesting that both p38 and ERK MAP kinase activation appear to be necessary for AP-1 activation by LPG. Lipophosphoglycan induced IL-12 production and generation of nitric oxide in murine macrophages. These results demonstrate that L. donovani LPG activates pro-inflammatory, endotoxin-like response pathway in J774A.1 macrophages and the interaction may play a pivotal role in the elimination of the parasite.     

Involvement of MAP kinases in apoptosis of macrophage treated with Trichomonas vaginalis

A primitive protozoan parasite Trichomonas vaginalis selectively activates the signal transduction pathways in macrophages (RAW264.7). This study evaluated the correlation of these signaling pathways and T. vaginalis-induced cell apoptosis. In macrophages infected with T. vaginalis, apoptosis was assessed on the basis of DNA fragmentation on agarose gel electrophoresis. Infection of macrophages with T. vaginalis induced tyrosine phosphorylation of several proteins. Infected cells with T. vaginalis were shown to associate with phosphorylation of the extracellular signal-regulated (ERK)1/2 kinase, p38, c-Jun N-terminal kinase (JNK) mitogen-activated protein (MAP) kinases on Western blot analysis. The present finding also demonstrated a link between the ERK1/2, JNK and p38 apoptotic pathways that was modulated by T. vaginalis infection.     

Role of caspases in dexamethasone-induced apoptosis and activation of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase in human eosinophils

Eosinophils are the principal effector cells for the pathogenesis of allergic inflammation. Glucocorticoids such as dexamethasone have long been used therapeutically for eosinophilia in allergic inflammation by inducing eosinophil apoptosis, but little is known about the intracellular mechanisms mediating dexamethasone-induced apoptosis. In the present study, we investigated the effect of dexamethasone on three mitogen-activated protein kinases (MAPK) involved in the intracellular signalling pathway: c-Jun NH2-terminal kinase (JNK), p38 MAPK and extracellular signal-regulated kinase (ERK). We found that dexamethasone could activate JNK and p38 MAPK in a time-dependent manner but not ERK. Further, SB 203580, a specific p38 MAPK inhibitor, was additive with dexamethasone in inducing eosinophil apoptosis, while JNK1/2 antisense phosphorothioate oligodeoxynucleotides did not show any significant effect. These suggest that dexamethasone-induced JNK1/2 and p38 MAPK activation are not crucial to the induction of apoptosis. Pretreatment of eosinophils with benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (Z-VAD.FMK), a broad-spectrum caspase inhibitor, could inhibit dexamethasone-induced apoptosis in eosinophils dose-dependently. Moreover, Z-VAD.FMK partially inhibited dexamethasone-activated JNK and p38 MAPK activities. However, dexamethasone treatment did not activate specific caspase-3, -8 activity in eosinophils compared with spontaneous apoptosis. We therefore conclude that dexamethasone-induced apoptosis and activation of JNK and p38 MAPK activity in eosinophils are regulated by caspases but not through the common apoptosis-related caspase-3, -8 as in other cell types. Elucidation of the important role of caspases in eosinophil apoptosis may facilitate the development of more specific and effective treatment for allergic inflammation.     

p38 MAPK- Pim-3通路可能介导预处理对抗心肌细胞缺氧/复氧损伤

目的： 研究MAPK通路在原癌基因Pim-3抗心肌急性缺氧复氧损伤中的作用。方法：采用原代培养新生大鼠的心肌细胞,随机分为4组：正常对照组（control）、缺氧复氧组(A/R)、缺氧预适应组(APC+A/R)、阻断剂组。在缺氧预处理前分别用终浓度为10 μmol/L SB203850(p38 MAPK阻断剂)、U0126（ERK1/2阻断剂）、SP600125（SAPK/JNK阻断剂）与细胞孵育30 min。实验结束后测定MAPKs通路中ERK1/2、JNK、p38 MAPK 磷酸化蛋白表达水平及Pim-3蛋白的表达水平,同时检测培养液中乳酸脱氢酶(LDH) 活性、四唑盐（MTT）比色试验测定细胞存活率、TUNEL法检测细胞凋亡。结果： SB203850、U0126、SP600125能分别取消由APC或A/R所诱导ERK1/2、JNK、p38 MAPK的磷酸化水平的升高;由APC所诱导的Pim-3表达的升高在p38 MAPK通路被阻断后明显下调(P<0.01),并且心肌细胞LDH值升高,细胞存活率则下降,心肌细胞的凋亡指数升高。结论： p38 MAPK的激活可上调原癌基因Pim-3的表达,从而可能对心肌细胞起到保护作用。     

Differential modulation by exogenous carbon monoxide of TNF-alpha stimulated mitogen-activated protein kinases in rat pulmonary artery endothelial cells

Heme oxygenase-1 (HO-1) is an enzyme that is highly inducible by various cellular stressors, especially oxidant injury. Our laboratory and others have demonstrated that induction of HO-1 exerts an antiinflammatory effect both in vitro and in vivo. We hypothesized that carbon monoxide (CO), a major catalytic byproduct of heme catalysis by HO-1, may mediate this antiinflammatory effect by modulating signal transduction pathways, in particular the mitogen-activated protein (MAP) kinase pathway. Confluent primary cultures of rat pulmonary artery endothelial cells (RPAEC) were treated with tumor necrosis factor-alpha (TNF-alpha; 50 ng/ml), and whole-cell extracts were assayed for phosphorylated ERK1/2, JNK1/2, and p38 MAP kinases. These three major MAP kinase pathways were activated by TNF-alpha in a time-dependent manner. RPAEC treated with TNF-alpha in the presence of a low concentration of CO (1%) exhibited marked attenuation of the phosphorylation of ERK1/2 MAP kinase when compared with cells treated with TNF-alpha alone. A similar effect was seen on the upstream MEK 1/2 kinase. Interestingly, CO (1%) accentuated TNF-alpha-induced phosphorylated p38 MAP kinase. These effects of exogenous CO on the ERK1/2 and p38 systems could be replicated by overexpression of HO-1 in RPAEC, using an adenoviral vector. As these MAP kinases are implicated in the regulation of various inflammatory molecules and adhesion molecules, our data provide a potential mechanism by which HO-1, acting via CO, may modulate the inflammatory response by differential activation of the MAP kinase pathway.     

Kinases and kinase signaling pathways: potential therapeutic targets in Parkinson's disease

Complex molecular mechanisms underlying the pathogenesis of Parkinson's disease (PD) are gradually being elucidated. Accumulating genetic evidence implicates dysfunction of kinase activities and phosphorylation pathways in the pathogenesis of PD. Causative and risk gene products associated with PD include protein kinases (such as PINK1, LRRK2 and GAK) and proteins related phosphorylation signaling pathways (such as SNCA, DJ-1). PINK1, LRRK2 and several PD gene products have been associated with mitogen-activated protein (MAP) and protein kinase B (AKT) kinase signaling pathways. C-Jun N-terminal kinase (JNK), extracellular signal-regulated kinases (ERK) and p38, signaling pathways downstream of MAP, are particularly important in PD. JNK and p38 play an integral role in neuronal death. Targeting JNK or p38 signaling may offer an effective therapy for PD. Inhibitors of the ERK signaling pathway, which plays an important role in the development of l-DOPA-induced dyskinesia (LID), have been shown to attenuate this condition in animal models. In this review, we summarize experimental evidence gathered over the last decade on the role of PINK1, LRRK2 and GAK and their related phosphorylation signaling pathways (JNK, ERK, p38 and PI3K/AKT) in PD. It is speculated that improvement or modulation of these signaling pathways will reveal potential therapeutic targets for attenuation of the cardinal symptoms and motor complications in patients with PD in the future.     

Beta 1/beta 3 integrin ligation is uncoupled from ERK1/ERK2 activation in cytotoxic T lymphocytes

beta 3 integrins mediate fibronectin binding and enhanced activation of cytotoxic T lymphocytes (CTL). The intracellular signals initiated by beta 3 integrins in lymphocytes are not well characterized, but in many cell types, beta 1 integrin ligation activates mitogen-activated protein (MAP) kinases. In the present study, we find that fibronectin can synergize with very low levels of CD3 stimulation to activate the extracellular signal-regulated kinase (ERK)1 and ERK2 MAP kinases but that fibronectin alone induces no detectable MAP kinase activation in CTL. Surprisingly, antibodies to beta1 or beta 3 integrins were also unable to stimulate MAP kinase activation, suggesting that although beta 1 integrins are capable of stimulating MAP kinase activation in other cells, they cannot do so in CTL. In CTL, phosphorylation of proline-rich tyrosine kinase 2 downstream of integrin stimulation did not result in recruitment of the adaptor protein Grb2. Additionally, we examined the role of MAP kinases in regulating integrin-mediated adhesion. Anti-CD3-triggered adhesion to fibronectin was largely insensitive to the MAP kinase kinase inhibitor PD98059. Triggered cell-spreading on fibronectin was inhibited by PD98059 but not by U0126. In summary, ligation of beta 3 integrin by antibodies or fibronectin or of beta1 integrin by monoclonal antibodies fails to activate ERK MAP kinases, but integrin ligation synergizes with T cell receptor stimulation upstream of MAP kinases.     

CP-64131, an aminobenzazepine with cytokine-like properties, stimulates human neutrophil functions through the p38-MAPK pathway

CP-64131 (CP), an aminobenzazepine with cytokine-like, physiologic effects similar to granulocyte-colony stimulating factor (G-CSF) and granulocyte macrophage (GM)-CSF, increases the number of neutrophils and stimulates marrow recovery after doxirubicin ablation. CP can also function as a neutrophil agonist, like formyl-Met-leu-Phe (fMLP). In these studies, we show that CP is unique in that it stimulates the p38-mitogen-activated protein kinase (MAPK) pathway but not extracellular signal-regulated kinase (ERK)1/2 or c-jun N-terminal kinase MAPKs in human neutrophils from peripheral blood. This is in contrast to other neutrophil agonists such as fMLP, interleukin (IL)-8, or GM-CSF, which stimulate multiple MAPK pathways. Like fMLP and IL-8, CP is capable of stimulating superoxide (O2-) production, CD11b expression, and cell polarization in human neutrophils. CP-stimulated O2- production is completely dependent on p38-MAPK activation, as determined by sensitivity to the p38-MAPK inhibitor SB203580. In contrast, SB203580 only partially inhibits expression of CD11b and has no effect on cell polarization stimulated by CP. Therefore, CP treatment of neutrophils activates p38-MAPK but has effects independent of p38-MAPK activation. In human embryonic kidney 293 cells, a human kidney epithelial cell line CP stimulates p38-MAPK and modestly activates ERK1/2. The findings define CP as a novel, small molecule, which has little cellular toxicity in vitro. CP has the ability to activate specific MAPK pathways in different cell types and should prove to be an effective agonist in combination with inhibitors to study biological responses regulated by MAPKs.     

Differences in cell activation by Chlamydophila pneumoniae and Chlamydia trachomatis infection in human endothelial cells

Seroepidemiological studies and demonstration of viable bacteria in atherosclerotic plaques have linked Chlamydophila pneumoniae infection to the development of chronic vascular lesions and coronary heart disease. In this study, we characterized C. pneumoniae-mediated effects on human endothelial cells and demonstrated enhanced phosphorylation and activation of the endothelial mitogen-activated protein kinase (MAPK) family members extracellular receptor kinase (ERK1/2), p38-MAPK, and c-Jun-NH2 kinase (JNK). Subsequent interleukin-8 (IL-8) expression was dependent on p38-MAPK and ERK1/2 activation as demonstrated by preincubation of endothelial cells with specific inhibitors for the p38-MAPK (SB202190) or ERK (U0126) pathway. Inhibition of either MAPK had almost no effect on intercellular cell adhesion molecule 1 (ICAM-1) expression. While Chlamydia trachomatis was also able to infect endothelial cells, it did not induce the expression of endothelial IL-8 or ICAM-1. These effects were specific for a direct stimulation with viable C. pneumoniae and independent of paracrine release of endothelial cell-derived mediators like platelet-activating factor, NO, prostaglandins, or leukotrienes. Thus, C. pneumoniae triggers an early signal transduction cascade in target cells that could lead to endothelial cell activation, inflammation, and thrombosis, which in turn may result in or promote atherosclerosis.     

p38 mitogen-activated protein kinase regulates growth factor-induced mitogenesis of rat pulmonary myofibroblasts

Myofibroblast proliferation is a central feature of pulmonary fibrogenesis. Several growth factors, including platelet-derived growth factor (PDGF) and epidermal growth factor (EGF), stimulate myofibroblast growth by activating extracellular signal regulated kinases 1 and 2 (ERK1/2). In this report, we demonstrate that PDGF-BB and EGF also activate the p38 mitogen-activated protein (MAP) kinase. Inhibition of p38 activity with the pyridinylimidazole compound SB203580 enhanced both PDGF-BB and EGF-stimulated DNA synthesis in rat lung myofibroblasts. ERK1/2 phosphorylation in response to either PDGF-BB or EGF treatment was significantly increased by pretreatment of cells with SB203580. We also demonstrated that ERK1/2-induced phosphorylation of PHAS-1 substrate was enhanced by inhibition of p38 MAP kinase with SB203580. However, SB203580 did not significantly increase growth factor-induced activation of MEK, the upstream kinase that phosphorylates ERK1/2. p38 MAP kinase was co-immunoprecipitated with ERK-1/2 following growth factor stimulation. Collectively, these data demonstrate that p38 MAP kinase activation negatively regulates PDGF- and EGF-mediated growth responses by directly interacting with ERK1/2 and suppressing its phosphorylation.     

Sodium salicylate-induced apoptosis of human peripheral blood eosinophils is independent of the activation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase

BACKGROUND: It has been shown that the inhibition of eosinophilic apoptosis is an important mechanism for the development of blood and tissue eosinophilia in allergic diseases. Considerable attention has recently been focused on the role played by different intracellular kinase cascades in the control of apoptosis. In the present study, we investigated the effect of sodium salicylate (NaSal), a nonsteroidal anti-inflammatory drug, on mitogen-activated protein kinases (MAPK) and apoptosis of human eosinophils. METHODS: Human blood eosinophils were purified from buffy coat. NaSal-induced apoptosis of eosinophils was assessed by morphological changes and Annexin-V binding assay. Changes of MAPK activity upon treatment with NaSal were measured by kinase activity assay and Western blot. RESULTS: NaSal could induce apoptosis of human blood eosinophils in a dose- and time-dependent manner. It could also activate c-Jun N-terminal kinase (JNK) and p38 MAPK but not extracellular signal-regulated protein kinase (ERK) activity within 1 h. Pretreatment of eosinophils with p38 MAPK and JNK anti-sense (AS) phosphorothioate oligodeoxynucleotides (ODN) or specific p38 MAPK inhibitor SB 203580 did not have any significant effect on NaSal-induced apoptosis. However, ERK AS ODNs could trigger the apoptosis of normal eosinophils. CONCLUSION: There is no direct relationship between the activation of JNK and p38 MAPK pathways and NaSal-induced apoptosis in human peripheral blood eosinophils.