CXCL9 and 11 in patients with pulmonary sarcoidosis: a role of alveolar macrophages

Abstract

SummaryInterferon-inducible protein-10 (IP-10)/CXCL10, which is a ligand for CXC chemokine receptor 3 (CXCR3), is known to be involved in the pathogenesis of pulmonary sarcoidosis. However, the roles of monokine induced by interferon g (Mig)/CXCL9 and interferon-inducible T cell a chemoattractant (I-TAC)/CXCL11, which are also CXCR3 ligands, remain unclear. Mig/ CXCL9, IP-10/CXCL10 and I-TAC/CXCL11 in both bronchoalveolar lavage fluid (BALF) and serum in patients with pulmonary sarcoidosis were measured by enzyme-linked immunosorbent assay (ELISA). The expression of these chemokines in alveolar macrophages was examined using ELISA, quantitative real-time polymerase chain reaction and immunostaining. In BALF, Mig/CXCL9 and IP-10/CXCL10 were significantly elevated in stage II sarcoidosis as compared with the levels in healthy volunteers. In serum, Mig/CXCL9 and I-TAC/CXCL11 were increased in stage II of the disease. The levels of all CXCR3 ligands in BALF were correlated with the numbers of both total and CD4 + lymphocytes. Alveolar macrophages were stained positive for all CXCR3 ligands and produced increased amounts of these chemokines. Positive staining of the three chemokines was also observed in the epithelioid and giant cells in the sarcoid lungs. These findings suggest that Mig/CXCL9 and I-TAC/ CXCL11 as well as IP-10/CXCL10 play important roles in the accumulation of Th1 lymphocytes in sarcoid lungs.

T-helper cell type-1 transcription factor T-bet is upregulated in pulmonary sarcoidosis

“…Of the studied chemokine receptors, we observed a strong correlation between T-bet and CXCR6, a receptor co-expressed on CXCR3 T-cells in sarcoidosis [4]. Furthermore, a strong correlation was observed between T-bet and CCL5 and CXCL10, two chemokines that play an important role in the recruitment of T-cells to the sarcoid lungs [4,[15][16][17]19]. Additionally, we observed a strong association between T-bet and IL-2R/IL-15Rb (CD122) in our sarcoidosis patients; this association has been already reported in animal cell cultures [5,7].…”

“…Secondly, we aimed to address the question as to whether there is evidence supporting the theory of T-bet modulation of CXCR3 and IFN-c gene expression in sarcoid lungs by performing correlation analyses of their mRNA expression profiles in BAL cells. Finally, we investigated the relationship of T-bet with a range of sarcoidosis-associated genes, namely: 1) ligands of CXCR3 receptor (CXCL9, CXCL10 and CXCL11) [14][15][16][17]; 2) chemokines CCL2 and CCL5 [18,19]; 3) chemokine receptors CCR2, CCR5 and CXCR6 [4,10,20,21]; and 4) b-chain subunit of IL-2R and IL-15R receptors [10,22]. Herein, we report upregulation of T-bet in sarcoidosis and its relationship with some sarcoid-associated molecules.…”

“…To address the role for T-bet as a plausible regulator of immune mediators in sarcoidosis, we studied its relationship with cytokines and their receptors that have been previously implicated in the pathogenesis of sarcoidosis. Of these ''sarcoidosis-associated'' genes we mainly focused on chemokines directing the trafficking of activated T-cells into sarcoid lungs, such as CCL2, CCL5, CXCL9, CXCL10 and CXCL11 [14][15][16][17][18][19], and chemokine receptors, CC chemokine ligand (CCR)5 [10] and CXCR6 [4] preferentially expressed on activated lymphocytes.…”

Longitudinal analysis of sarcoidosis blood transcriptomic signatures and disease outcomes

“…CXCL9 is an IFN-cinducible chemokine that, upon binding to its receptor CXCR3, facilitates recruitment of T-cells to inflamed tissues in human autoimmune diseases. We and others have demonstrated elevations in CXCL9 protein levels in sarcoidosis sera [15,21], bronchoalveolar lavage (BAL) fluid [15,21,33] and granulomas [34]. We further show that CXCL9 gene expression inversely correlated with DLCO % predicted, independent of time from diagnosis.…”

Lactobacillus paracasei and Lactobacillus plantarum strains downregulate proinflammatory genes in an ex vivo system of cultured human colonic mucosa

“…The primer sequences were as follows (sense and antisense, respectively): interleukin 2 (IL2): 5-TCCCAAACTCACC AGGATGCTCACA-3, 5-GCACTTCCTCCAGAGGTTTG AGTTCT-3; interleukin 17A (IL17A): 5-TTCCCCCG GACTGTGATGGT-3, 5-CGGCACTTTGCCTCCCAG AT-3; guanylate-binding protein 1, interferon-inducible (GBP1): 5-TCCCAGCCCTACAACTTCGG-3, 5-TGCCA TGTCCAGGCTGTTCC-3. The primer sequences for interleukin 2 receptor a (IL2RA), chemokine (C-X-C motif) ligand (CXCL) 11, ubiquitin D (UBD), tumor necrosis factor receptor superfamily member 9 (TNFRSF9), interferon c (IFN-c) and CXCL9 have been previously described (Nishioka et al 2007;Pattyn et al 2003;Spandidos et al 2008;Wang and Seed 2003).…”