Eotaxin/CCL11 Suppresses IL-8/CXCL8 Secretion from Human Dermal Microvascular Endothelial Cells

Lukacs, Nicholas W.; Kunkel, Steven L.

doi:10.4049/jimmunol.168.6.2887

Cited by 33 publications

(23 citation statements)

References 61 publications

(43 reference statements)

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“…Although chemokine up-regulation induced by CCL11 was not inhibited in this study by CCR3 antagonism, autoregulation of CCR3 by CCL11 and CCL26 has been previously reported in normal bronchial EC and in the alveolar EC line A549, respectively (50,51), suggesting the existence of a complex regulatory feedback system, similar to that documented for other receptors, such as the high-affinity IgE receptor (52,53). A complex role of CCR3 in regulating local chemokine levels is further suggested by the reported involvement of the CCR3 expressed on human dermal microvascular EC in mediating the suppression of TNF-␣-induced CXCL8 in cells treated with CCL11 (54).…”

Section: Discussionsupporting

confidence: 59%

Functional Analysis of the Chemokine Receptor CCR3 on Airway Epithelial Cells

Beck¹,

Tancowny²,

Brummet³

et al. 2006

The Journal of Immunology

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The function of chemokine receptors on structural cells is only partially known. We previously reported the expression of a functional CCR3 receptor on airway epithelial cells (EC). We speculated that CCR3 might drive wound repair and expression of inflammatory genes in epithelium. The human airway EC lines BEAS-2B, 16-HBE, and primary bronchial EC were used to test the effect of in vitro challenge with the CCR3 ligands CCL11/eotaxin, CCL24/eotaxin-2, or CCL26/eotaxin-3 on 1) wound repair, using an established wound model; 2) cell proliferation and chemotaxis, using specific fluorometric assays; and 3) gene expression, using pathway-specific arrays for inflammatory and profibrotic cytokines, chemokines, and chemokine receptor genes. Agonist specificity was tested by cell pretreatment with an AstraZeneca CCR3 antagonist (10−8 – 10−6 M). CCL24 challenge significantly accelerated epithelial wound closure, with similar effects exerted by CCL11 and CCL26. This effect was time dependent, submaximal at 1 nM, and comparable in potency to epidermal growth factor. CCL24 induced a concentration-dependent increase in EC proliferation and chemotaxis, with significant effects observed at 10 nM. The AstraZeneca compound selectively inhibited these CCL24-mediated responses. CCL11 induced the up-regulation of several profibrogenic molecules such as fibroblast growth factor 1 and 5 and of several CC and CXC chemokines. Epithelial immunostaining for CCR3 was stronger in bronchial biopsies of asthmatics displaying marked inflammatory changes than in nondiseased samples. Epithelial CCR3 participates in key functions for wound repair, amplifies the expression of profibrogenic and chemokine transcripts, and appears up-regulated in inflamed asthmatic airways.

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Section: Discussionsupporting

confidence: 59%

Functional Analysis of the Chemokine Receptor CCR3 on Airway Epithelial Cells

Beck¹,

Tancowny²,

Brummet³

et al. 2006

The Journal of Immunology

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“…Because an earlier study in primary bronchial epithelial cells did not report similar findings (45), the effect of IL-17A may be cell specific. Besides its role in attracting eosinophils, eotaxin-1/CCL11 has been shown to inhibit neutrophil recruitment in a mouse model of endoxemia (46) and down-regulate CXC chemokines particularly IL-8/CXCL8 in human dermal microvascular endothelial cells (47). In light of prior evidence and present data, it is tempting to speculate that IL-17A-mediated eotaxin-1/CCL11 release may down-regulate exaggerated neutrophilic inflammation by suppressing CXC chemokine release during acute inflammation, hence creating a negative feedback to establish tissue homeostasis.…”

Section: Discussionmentioning

confidence: 99%

IL-17A Induces Eotaxin-1/CC Chemokine Ligand 11 Expression in Human Airway Smooth Muscle Cells: Role of MAPK (Erk1/2, JNK, and p38) Pathways

Rahman¹,

Yamasaki

Yang³

et al. 2006

The Journal of Immunology

120

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Recently, IL-17A has been shown to be expressed in higher levels in respiratory secretions from asthmatics and correlated with airway hyperresponsiveness. Although these studies raise the possibility that IL-17A may influence allergic disease, the mechanisms remain unknown. In this study, we investigated the molecular mechanisms involved in IL-17A-mediated CC chemokine (eotaxin-1/CCL11) production from human airway smooth muscle (ASM) cells. We found that incubation of human ASM cells with rIL-17A resulted in a significant increase of eotaxin-1/CCL11 release from ASM cells that was reduced by neutralizing anti-IL-17A mAb. Moreover, IL-17A significantly induced eotaxin-1/CCL11 release and mRNA expression, an effect that was abrogated with cycloheximide and actinomycin D treatment. Furthermore, transfection studies using a luciferase-driven reporter construct containing eotaxin-1/CCL11 proximal promoter showed that IL-17A induced eotaxin-1/CCL11 at the transcriptional level. IL-17A also enhanced significantly IL-1β-mediated eotaxin-1/CCL11 mRNA, protein release, and promoter activity in ASM cells. Primary human ASM cells pretreated with inhibitors of MAPK p38, p42/p44 ERK, JNK, or JAK but not PI3K, showed a significant decrease in eotaxin-1/CCL11 release upon IL-17A treatment. In addition, IL-17A mediated rapid phosphorylation of MAPK (p38, JNK, and p42/44 ERK) and STAT-3 but not STAT-6 or STAT-5 in ASM cells. Taken together, our data provide the first evidence of IL-17A-induced eotaxin-1/CCL11 expression in ASM cells via MAPK (p38, p42/p44 ERK, JNK) signaling pathways. Our results raise the possibility that IL-17A may play a role in allergic asthma by inducing eotaxin-1/CCL11 production.

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“…The CC chemokine eotaxin/CCL11 is known to bind to the receptor CCR3 on eosinophils and Th2-type lymphocytes [151]. Increased levels of eotaxin are associated with the increased severity of lethargy, stereotypy, and hyperactivity in ASD subjects [149].…”

Section: Eotaxinmentioning

confidence: 99%

Neuroimmune Alterations in Autism: A Translational Analysis Focusing on the Animal Model of Autism Induced by Prenatal Exposure to Valproic Acid

Deckmann

Schwingel

Fontes-Dutra

et al. 2018

Neuroimmunomodulation

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Autism spectrum disorder (ASD) is a highly prevalent developmental disorder characterized by deficits in communication and social interaction and in stereotyped or repetitive behaviors. Besides the classical behavioral dyad, several comorbidities are frequently present in patients with ASD, such as anxiety, epilepsy, sleep disturbances, and gastrointestinal tract dysfunction. Although the etiology of ASD remains unclear, there is supporting evidence for the involvement of both genetic and environmental factors. Valproic acid (VPA) is an anticonvulsant and mood stabilizer that, when used during the gestational period, increases the risk of ASD in the offspring. The animal model of autism induced by prenatal exposure to VPA demonstrates important structural and behavioral features that can be observed in individuals with autism; it is thus an excellent tool for testing new drug targets and developing novel behavioral and drug therapies. In addition, immunological alterations during pregnancy could affect the developing embryo because immune molecules can pass through the placental barrier. In fact, exposure to pathogens during the pregnancy is a known risk factor for ASD, and maternal immune activation can lead to autistic-like features in animals. Interestingly, neuroimmune alterations are common in both autistic individuals and in animal models of ASD. We summarize here the important alterations in inflammatory markers, such as cytokines and chemokines, in patients with ASD and in the VPA animal model.

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Eotaxin/CCL11 Suppresses IL-8/CXCL8 Secretion from Human Dermal Microvascular Endothelial Cells

Cited by 33 publications

References 61 publications

Functional Analysis of the Chemokine Receptor CCR3 on Airway Epithelial Cells

Functional Analysis of the Chemokine Receptor CCR3 on Airway Epithelial Cells

IL-17A Induces Eotaxin-1/CC Chemokine Ligand 11 Expression in Human Airway Smooth Muscle Cells: Role of MAPK (Erk1/2, JNK, and p38) Pathways

Neuroimmune Alterations in Autism: A Translational Analysis Focusing on the Animal Model of Autism Induced by Prenatal Exposure to Valproic Acid

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