The Role of the Th2 CC Chemokine Ligand CCL17 in Pulmonary Fibrosis

Belperio, John A.; Dy, Maria; Murray, Lynne A.; Burdick, Marie D.; Xue, Ying; Strieter, Robert M.; Keane, Michael P.

doi:10.4049/jimmunol.173.7.4692

Cited by 161 publications

(141 citation statements)

References 49 publications

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“…The recent observation (24) that effective ablation of eosinophilopoiesis with an anti-IL-5 Ab does not ameliorate asthma, at least in the short term, has raised the specter that cellular infiltration may not be the sole, or even the primary, cause of the clinical features of the disease. As with cytokines, the effects of chemokines on smooth muscle proliferation, angiogenesis, mucus metaplasia, and structural protein synthesis (2,8,25) may also be significant in this regard.…”

Section: Discussionmentioning

confidence: 99%

Thymic Stromal Lymphopoietin Expression Is Increased in Asthmatic Airways and Correlates with Expression of Th2-Attracting Chemokines and Disease Severity

Ying

O’Connor

Ratoff

et al. 2005

The Journal of Immunology

783

644

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Thymic stromal lymphopoietin (TSLP) is said to increase expression of chemokines attracting Th2 T cells. We hypothesized that asthma is characterized by elevated bronchial mucosal expression of TSLP and Th2-attracting, but not Th1-attracting, chemokines as compared with controls, with selective accumulation of cells bearing receptors for these chemokines. We used in situ hybridization and immunohistochemistry to examine the expression and cellular provenance of TSLP, Th2-attracting (thymus and activation-regulated chemokine (TARC)/CCL17, macrophage-derived chemokine (MDC)/CCL22, I-309/CCL1) and Th1-attracting (IFN-γ-inducible protein 10 (IP-10)/CXCL10, IFN-inducible T cell α-chemoattractant (I-TAC)/CXCL11) chemokines and expression of their receptors CCR4, CCR8, and CXCR3 in bronchial biopsies from 20 asthmatics and 15 normal controls. The numbers of cells within the bronchial epithelium and submucosa expressing mRNA for TSLP, TARC/CCL17, MDC/CCL22, and IP-10/CXCL10, but not I-TAC/CXCL11 and I-309/CCL1, were significantly increased in asthmatics as compared with controls (p ≤ 0.018). TSLP and TARC/CCL17 expression correlated with airway obstruction. Although the total numbers of cells expressing CCR4, CCR8, and CXCR3 did not significantly differ in the asthmatics and controls, there was evidence of selective infiltration of CD4+/CCR4+ T cells in the asthmatic biopsies which correlated with TARC and MDC expression and airway obstruction. Epithelial cells, endothelial cells, neutrophils, macrophages, and mast cells were significant sources of TSLP and chemokines. Our data implicate TSLP, TARC/CCL17, MDC/CCL22, and IP-10/CXCL10 in asthma pathogenesis. These may act partly through selective development and retention, or recruitment of Th2 cells bearing their receptors.

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Section: Discussionmentioning

confidence: 99%

Thymic Stromal Lymphopoietin Expression Is Increased in Asthmatic Airways and Correlates with Expression of Th2-Attracting Chemokines and Disease Severity

Ying

O’Connor

Ratoff

et al. 2005

The Journal of Immunology

783

644

View full text Add to dashboard Cite

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“…There are data from experimental models that support the importance of the Th2 response in pulmonary fibrosis. CC chemokine ligand (CCL)17 and CCL22 are associated with a Th2 profile and are significantly elevated in bleomycin-induced pulmonary fibrosis [1]. In addition, their receptor CCR4 is significantly elevated in bleomycin-treated mice, predominantly on macrophages.…”

Section: Type-1 and Type-2 T-cell Responsementioning

confidence: 98%

The role of chemokines and cytokines in lung fibrosis

Keane¹

2008

Eur Respir Rev

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Idiopathic pulmonary fibrosis (IPF) exhibits a complex and poorly understood pathogenesis. Overt inflammation in the lungs of patients with established IPF is absent, and classic anti-inflammatory therapies are inefficacious; however, inflammation may contribute to the disruption of the normal alveolar architecture, allowing interaction between fibroblasts and the epithelium. The polarisation of the inflammatory response toward a type-2 helper T-cell phenotype may also be important in the development of pulmonary fibrosis, as fibroproliferation could be favoured over repair. Furthermore, evidence has emerged regarding an imbalance between angiogenic and angiostatic chemokine levels, leading to an overall angiogenic pattern of expression in both animal models and tissue specimens from IPF patients. The precise role of vascular remodelling in IPF remains to be determined. Therefore, numerous questions exist regarding the role and importance of chemokines and cytokines in pulmonary fibrosis. Further investigation is required to facilitate the elucidation of IPF pathogenesis and identification of novel targets for treatment of this dismal disease.

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“…These changes at the surface were accompanied by a significant increase in IL-10 transcription. Interestingly, PDL-1 has been shown to be up-regulated by AAMs during helminth infections and was demonstrated as an AAM mechanism of T cell suppression [61,62] Lung AAMs also appear to exert control on the pulmonary environment by increasing the transcription of genes encoding chemokines such as CCL11, CCL17, and CCL24, which are known to be involved in cellular recruitment during Th2 immune responses [63][64][65]. CCL17, which was up-regulated more than ten-fold on each day of infection, has been shown to be induced by AAMs as a result of IL-4 signaling [66].…”

Section: Discussionmentioning

confidence: 99%

Dynamics of lung macrophage activation in response to helminth infection

Siracusa

Reece

Urban

et al. 2008

Journal of Leukocyte Biology

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Most of our understanding of the development and phenotype of alternatively activated macrophages (AAMs) has been obtained from studies investigating the response of bone marrow-and peritoneal-derived cells to IL-4 or IL-13 stimulation. Comparatively little is known about the development of AAMs in the lungs, and how the complex signals associated with pulmonary inflammation influence the AAM phenotype. Here, we use Nippostrongylus brasiliensis to initiate AAM development and define the dynamics of surface molecules, gene expression, and cell function of macrophages isolated from lung tissue at different times postinfection (PI). Initially, lung macrophages take on a foamy phenotype, up-regulate MHC and costimulatory molecules, express reduced levels of TNF and IL-12, and undergo proliferation. Cells isolated between days 8 and 15 PI adopt a dense, granular phenotype and exhibit reduced levels of costimulatory molecules and elevated levels of programmed death ligand-1 (PDL-1) and PDL-2 and an increase in IL-10 expression. Functionally, AAMs isolated on days 13-15 PI demonstrate an enhanced capacity to take up and sequester antigen. However, these same cells did not mediate antigen-specific T cell proliferation and dampened the proliferation of CD3/CD28-activated CD4 ؉ T cells. These data indicate that the alternative activation of macrophages in the lungs, although initiated by IL-4/IL-13, is a dynamic process that is likely to be influenced by other immune and nonimmune factors in the pulmonary environment. J.

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The Role of the Th2 CC Chemokine Ligand CCL17 in Pulmonary Fibrosis

Cited by 161 publications

References 49 publications

Thymic Stromal Lymphopoietin Expression Is Increased in Asthmatic Airways and Correlates with Expression of Th2-Attracting Chemokines and Disease Severity

Thymic Stromal Lymphopoietin Expression Is Increased in Asthmatic Airways and Correlates with Expression of Th2-Attracting Chemokines and Disease Severity

The role of chemokines and cytokines in lung fibrosis

Dynamics of lung macrophage activation in response to helminth infection

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