Inoue T, etal., Eur Respir J. 2004 Jul;24(1):49-56.
Pulmonary fibrosis is caused by various known and unknown aetiologies, but the key pathogenic mechanisms are still ill-defined. Chemokines are a large family of chemotactic cytokines that play pivotal roles in various inflammatory diseases. In the present study, the roles of chemokines in a rat mode
l of radiation pneumonitis/ pulmonary fibrosis were examined. Accumulation of inflammatory cells and pneumonitis were observed on day 28, and diffuse alveolar wall thickening with extensive fibrosis was observed on day 56. In addition to the previously reported CCL2 (macrophage chemoattractant protein-1) induction, selective upregulation of CCL22 (macrophage-derived chemokine) and CCL17 (thymus and activation-regulated chemokine) were demonstrated for the first time in the irradiated lung tissues. Immunohistochemically, it was demonstrated that CCL22 and CCL17 were localised primarily to alveolar macrophages, whereas their receptor CC chemokine receptor 4 (CCR4) was detected on alveolar lymphocytes and macrophages. On further analysis of bronchoalveolar lavage fluid from patients with idiopathic pulmonary fibrosis and sarcoidosis, elevated levels of CCL22, but not of CCL17, were observed in the idiopathic pulmonary fibrosis patients. Since these two chemokines play pivotal roles in various type-2 T-helper cell-dominant diseases, it was speculated that CCL22, and probably CCL17, are involved in the pathophysiology of radiation pneumonitis/pulmonary fibrosis and idiopathic pulmonary fibrosis through the recruitment of CC chemokine receptor 4-positive type-2 T-helper cells and alveolar macrophages.
BACKGROUND: Leprosy is characterized by polar clinical, histologic and immunological presentations. Previous immunologic studies of leprosy polarity were limited by the repertoire of cytokines known at the time. METHODOLOGY: We used a candidate gene approach to measure mRNA levels in skin biopsies f
rom leprosy lesions. mRNA from 24 chemokines and cytokines, and 6 immune cell type markers were measured from 85 Nepalese leprosy subjects. Selected findings were confirmed with immunohistochemistry. PRINCIPAL RESULTS: Expression of three soluble mediators (CCL18, CCL17 and IL-10) and one macrophage cell type marker (CD14) was significantly elevated in lepromatous (CCL18, IL-10 and CD14) or tuberculoid (CCL17) lesions. Higher CCL18 protein expression by immunohistochemistry and a trend in increased serum CCL18 in lepromatous lesions was observed. No cytokines were associated with erythema nodosum leprosum or Type I reversal reaction following multiple comparison correction. Hierarchical clustering suggested that CCL18 was correlated with cell markers CD209 and CD14, while neither CCL17 nor CCL18 were highly correlated with classical TH1 and TH2 cytokines. CONCLUSIONS: Our findings suggest that CCL17 and CCL18 dermal expression is associated with leprosy polarity.
Monick MM, etal., J Immunol. 2007 Aug 1;179(3):1648-58.
Respiratory syncytial virus (RSV) is a ubiquitous virus that preferentially infects airway epithelial cells, causing asthma exacerbations and severe disease in immunocompromised hosts. Acute RSV infection induces inflammation in the lung. Thymus- and activation-regulated chemokine (TARC) recruits Th
2 cells to sites of inflammation. We found that acute RSV infection of BALB/c mice increased TARC production in the lung. Immunization of BALB/c mice with individual RSV proteins can lead to the development of Th1- or Th2-biased T cell responses in the lung after RSV infection. We primed animals with a recombinant vaccinia virus expressing either the RSV fusion (F) protein or the RSV attachment (G) protein, inducing Th1- and Th2-biased pulmonary memory T cell responses, respectively. After RSV infection, TARC production significantly increased in the vaccinia virus G-primed animals only. These data suggest a positive feedback loop for TARC production between RSV infection and Th2 cytokines. RSV-infected lung epithelial cells cultured with IL-4 or IL-13 demonstrated a marked increase in the production of TARC. The synergistic effect of RSV and IL-4/IL-13 on TARC production reflected differential induction of NF kappa B and STAT6 by the two stimuli (both are in the TARC promoter). These findings demonstrate that RSV induces a chemokine TARC that has the potential to recruit Th2 cells to the lung.
Ritter M, etal., Biochem Biophys Res Commun. 2005 Aug 19;334(1):254-62.
TARC (CCL17) and MDC (CCL22) are well-known chemoattractants for Th2 cells. Here, we evaluated the role of both chemokines for cigarette smoke-induced airway inflammation. The expression profiles of MDC, TARC, and their receptor CCR4 were analyzed in models of a
cute and chronic cigarette smoke-induced airway inflammation that is characterized by a Th1 immune response. The results were compared to the expression of both chemokines in models of idiopathic pulmonary fibrosis and acute asthma, which are associated with a Th2 immune response. The expression of MDC and TARC was found to be elevated in all lung inflammation models. In contrast to the findings in the asthma and lung fibrosis models, the increased expression of MDC and TARC in the cigarette-smoke model was not associated with an increased infiltration of Th2 cells into smoke-treated lungs. Our data indicate that instead of Th2 cells, airway epithelial cells expressing CCR4 might be the principal targets for MDC and TARC released from alveolar macrophages during cigarette smoke-induced airway inflammation.
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronically progressive interstitial lung disease of unknown etiology. Previously, we have demonstrated the selective upregulation of the macrophage-derived chemokine CCL22 and the thymus activation-regulated chemokine CCL17
;'>CCL17 among chemokines, in a rat model of radiation pneumonitis/pulmonary fibrosis and preliminarily observed an increase in bronchoalveolar (BAL) fluid CCL22 levels of IPF patients. METHODS: We examined the expression of CCR4, a specific receptor for CCL22 and CCL17, in bronchoalveolar lavage (BAL) fluid cells, as well as the levels of CCL22 and CCL17, to elucidate their pathophysiological roles in pulmonary fibrosis. We also studied their immunohistochemical localization. RESULTS: BAL fluid CCL22 and CCL17 levels were significantly higher in patients with IPF than those with collagen vascular diseases and healthy volunteers, and there was a significant correlation between the levels of CCL22 and CCL17 in patients with IPF. CCL22 levels in the BAL fluid did not correlate with the total cell numbers, alveolar lymphocytes, or macrophages in BAL fluid. However, the CCL22 levels significantly correlated with the numbers of CCR4-expressing alveolar macrophages. By immunohistochemical and immunofluorescence analysis, localization of CCL22 and CCR4 to CD68-positive alveolar macrophages as well as that of CCL17 to hyperplastic epithelial cells were shown. Clinically, CCL22 BAL fluid levels inversely correlated with DLco/VA values in IPF patients. CONCLUSION: We speculated that locally overexpressed CCL22 may induce lung dysfunction through recruitment and activation of CCR4-positive alveolar macrophages.
Jakubzick C, etal., Am J Pathol. 2004 Oct;165(4):1211-21.
Controversy persists pertaining to the role of CCR4 ligands, namely CCL17 (or thymus and activation regulated chemokine; TARC) and CCL22 (or macrophage-derived chemokine; MDC), in Th2-type cytokine-dominated responses in the lung. Accordingly, the present study
addressed the relative role of each of these CC chemokines during an evolving pulmonary granulomatous response elicited by the intrapulmonary embolization of live Schistosoma mansoni eggs into S. mansoni-sensitized mice. CCL22 protein expression peaked at day 4, but CCL17 levels were not increased significantly at any time after egg challenge. CCR4 transcript and protein expression were highest at day 8 after egg embolization and CCR4 protein was prominently expressed in macrophages surrounding S. mansoni eggs. Systemic immunoneutralization of CCL22 from the time of egg injection into S. mansoni-sensitized mice for 8 days significantly decreased CCR4 protein expression, the eosinophil content, the overall size of the egg granuloma, and its hydroxyproline content. Whole lung levels of interferon-gamma were also significantly increased at day 8 in anti-CCL22-treated mice. The systemic immunoneutralization of CCL17 had a lesser effect on all of the granuloma parameters listed above, but this antibody treatment significantly decreased granuloma hydroxyproline content to a greater extent than the anti-CCL22 antibody treatment. In addition, the immunoneutralization of CCL17 significantly increased whole lung levels of interleukin (IL)-4, IL-5, IL-13, transforming growth factor-beta, IL-12, and tumor necrosis factor-alpha at day 8 after egg infusion. Thus, these studies demonstrate a major role for CCL22 and a lesser role for CCL17 during an evolving S. mansoni egg granuloma in the lung.
Zhu F, etal., Med Oncol. 2016 Feb;33(2):17. doi: 10.1007/s12032-016-0729-9. Epub 2016 Jan 19.
Alternatively activated macrophages (M2) can secrete chemokines, such as chemokine ligand 17 (CCL17), and are associated with promoting tumorigenesis of hepatocellular carcinoma (HCC). This study aimed at investigating the potential role of M2 and CCL17
ont-weight:700;'>CCL17 in progression of HCC. The levels of CCL17 expression in 90 HCC samples were characterized by tissue microarray and stratified for the postsurgical survival. MHCC97L cells were co-cultured with classically activated M1, M2 or CCL17-silencing M2(ccl17mute) or treated with conditional medium (CM) from these cells or CCL17 in vitro. The wound healing, invasion, viability and apoptosis of MHCC97L cells in vitro and tumor growth in vivo were determined. The stemness of MHCC97L cells was examined by sphere formation, flow cytometry and Western blot. The relative expression levels of epithelial-mesenchymal transition (EMT) factors and the Wnt/beta-catenin signaling were determined. Higher levels of intratumoral CCL17 expression were significantly associated with clinical pathological characteristics of HCC and with poorer overall survival rates in HCC patients (P < 0.05). High levels of CCR4 were detected in MHCC97L cells. Treatment with the CM from M2 or with CCL17 significantly enhanced the wound healing process, invasion and proliferation of MHCC97L cells in vitro. Co-implantation MHCC97L cells with M2 significantly promoted the growth of MHCC97L tumors in vivo. Co-culture with M2 or treatment with CCL17 enhanced the stemness, EMT process, the TGF-beta1 and Wnt/beta-catenin signaling in MHCC97L cells. CCL17 promotes the tumorigenesis of HCC and may be a potential biomarker and target for HCC prognosis and therapy.
