Expression and Cellular Provenance of Thymic Stromal Lymphopoietin and Chemokines in Patients with Severe Asthma and Chronic Obstructive Pulmonary Disease

Abstract

Asthma and chronic obstructive pulmonary disease (COPD) are associated with Th2 and Th1 differentiated T cells. The cytokine thymic stromal lymphopoietin (TSLP) promotes differentiation of Th2 T cells and secretion of chemokines which preferentially attract them. We hypothesized that there is distinct airways expression of TSLP and chemokines which preferentially attract Th1- and Th2-type T cells, and influx of T cells bearing their receptors in asthma and COPD. In situ hybridization, immunohistochemistry, and ELISA were used to examine the expression and cellular provenance of TSLP, Th2-attracting (TARC/CCL17, MDC/CCL22, I-309/CCL1), and Th1-attracting (IP-10/CXCL10, I-TAC/CXCL11) chemokines in the bronchial mucosa and bronchoalveolar lavage fluid of subjects with moderate/severe asthma, COPD, and controls. Cells expressing mRNA encoding TSLP, TARC/CCL17, MDC/CCL22, and IP-10/CXCL10, but not I-TAC/CXCL11 and I-309/CCL1, were significantly increased in severe asthma and COPD as compared with non-smoker controls (p < 0.02). This pattern was reflected in bronchoalveolar lavage fluid protein concentrations. Expression of the same chemokines was also increased in ex- and current smokers. The cellular sources of TSLP and chemokines were strikingly similar in severe asthma and COPD. The numbers of total bronchial mucosal T cells expressing the chemokine receptors CCR4, CCR8, and CXCR3 did not significantly differ in asthma, COPD, and controls. Both asthma and COPD are associated with elevated bronchial mucosal expression of TSLP and the same Th1- and Th2-attracting chemokines. Increased expression of these chemokines is not, however, associated with selective accumulation of T cells bearing their receptors.

Intranasal CpG Therapy Attenuated Experimental Fungal Asthma in a TLR9-Dependent and -Independent Manner

“…TGF-β and CCL17 have well-described roles in Th2-mediated airway inflammation [37], and both are prominently expressed and appear to have clear roles in the experimental asthma model studied herein [26,38]. The cytokine TSLP has not been examined in this model previously, but it is known to activate DCs and promotes the differentiation of Th2 T cells and secretion of Th2 cytokines and chemokines [39,40]. We observed that whole-lung levels of TGF-β were reduced IN CpG-treated TLR9+/+ mice and these findings are consistent with previous CpG studies in models of allergic airway disease [8,10,17].…”

TNF and IFN Synergistically Enhance Transcriptional Activation of CXCL10 in Human Airway Smooth Muscle Cells via STAT-1, NF- B, and the Transcriptional Coactivator CREB-binding Protein

“…CXCL10 is elevated in the airways of asthmatic patients and has been implicated in mast cell migration to the ASM bundles (3). CXCL10 also is elevated in the bronchial mucosa and broncho alveolar lavage (BAL) fluid of subjects with moderate/severe asthma, which is largely steroid-resistant (4). Enhanced CXCL10 secretion also has been demonstrated in COPD (5-7), and more recently, it has been reported that serum CXCL10 levels are increased to a greater extent in asthmatics with acute virus-induced asthma compared with nonvirus-induced acute asthma, and increased levels are predictive of virus-induced asthma exacerbations (8).…”

Increased Expression of Thymic Stromal Lymphopoietin and Its Receptor in Kimura's Disease

“…TSLP expression was upregulated in asthmatic airways, principally in epithelial cells, endothelial cells, neutrophils, macrophages, T lymphocytes, and mast cells [12]. The percentages of macrophages and mast cells expressing TSLP were significantly higher in asthmatics than in chronic obstructive pulmonary disease patients [27], although the stimuli that induce TSLP expression in macrophages remain unclear. Our results show that macrophages in the parotid lesions of KD patients are the major source of TSLP, and that TSLP from macrophages might cause Th2-type inflammatory responses in KD lesions.…”