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

Abstract

Upregulation of genes for interferon (IFN)-γ and CXC chemokine receptor (CXCR)3 expression, two crucial molecules in sarcoid inflammation and granuloma formation, is directly controlled by the T-helper (Th)1 transcription factor T-bet (T-box, expressed in T-cells). However, there is no information on T-bet expression in sarcoidosis or its relationship with “sarcoidosis-associated” genes.Therefore, we investigated expression of T-bet mRNA and, in parallel, a spectrum of genes known to be involved in sarcoidosis pathogenesis. Transcripts were determined in bronchoalveolar lavage (BAL) cells from 62 sarcoidosis patients and 25 controls by quantitative RT-PCR; T-bet protein was localised by immunohistochemistry.Patient’s BAL cells expressed higher mRNA T-bet levels than those of controls (mean±sdfold change 3.64±1.72; p=0.00006). T-bet mRNA expression did not vary between clinical phenotypes as assessed by chest radiography stage, presence/absence of Löfgren's syndrome, extrapulmonary/pulmonary involvement or progressing/remitting disease (p>0.05). T-bet mRNA expression correlated with expression of IFN-γ, CC chemokine ligand 5, CXC chemokine ligand (CXC)10, interleukin (IL)-2 receptor/IL-15 receptor β, CXCR3 and CXCR6 (p<0.01). T-bet protein was localised to alveolar macrophages and lymphocytes, tissue multinucleated giant cells, macrophages and lymphocytes.In pulmonary sarcoidosis, T-bet upregulation is associated with changes in expression of IFN-γ, CXCR3 and chemokines/receptors involved in the pathogenesis of sarcoidosis, which suggests a role for T-bet in this Th1 disease, including modulation of some sarcoidosis-associated genes.

IL-36γ/IL-1F9, an Innate T-bet Target in Myeloid Cells

“…Moreover, initiation of T-bet expression in Th17 cells may also favor transdifferentiation into Th1 cells, again strengthening the latter path of T cell polarization under the influence of T-bet (12). Current data furthermore indicate that T-bet expression is up-regulated in human inflammatory/M1 macrophages (13,14).…”

“…Inflammatory M1 Macrophages-T-bet expression has been detected on mRNA or mRNA/protein level in activated murine DC (7), human monocytes or monocyte-derived DC (6), and in human predendritic KG1 cells (20) as well as human inflammatory or M1 macrophages (13,14) but not in murine macrophages (7). To extend these current observations to human primary cells, experiments were performed using monocyte-derived DC and activated primary macrophages.…”

“…Exemplarily, CXCR3, CCL4, and NKG7 shall be quoted herein (41)(42)(43). However, expression of T-bet in activated DC (6, 7) and human monocytes/macrophages (13,14) likewise suggests a vital role for this transcription factor in myeloid cells and beyond that in innate immunity.…”

Gene expression profiles in granuloma tissue reveal novel diagnostic markers in sarcoidosis

“…Importantly, mutations within NOD2, which induces constitutive activation of the transcription factor NF-kB, were identified in early-onset sarcoidosis, (Kanazawa et al, 2005). Other candidate genes predicting susceptibility to sarcoidosis include genes involved in antigen processing and presentation by macrophages, factors affecting macrophage activation, T cell activation, and in injury repair (Kriegova et al, 2011). Candidate antigens that may trigger granulomatous inflammation in sarcoidosis include bacterial proteins from Mycobacterium tuberculosis and propionibacteria and β-glucan, a cell wall constituent of fungi (Ishige et al, 1999; Song et al, 2005; Terčelj et al, 2014).…”

“…The immune response in sarcoidosis is primarily mediated by the type I inflammatory cytokine pathway, which is promoted by NF-kB and STAT1 dependent signaling (Iannuzzi and Fontana, 2011; Miotto et al, 2001). The transcription factor T-bet is elevated in sarcoidosis and promotes Th1 specification through IL-12 and IFNγ signaling (Kriegova et al, 2011). Importantly, IFNγ is elevated in sarcoidois and mediates activation of signal transducer and activator of transcription-1 (STAT1) that is central in mounting a type I response by promoting expression of interferon-regulatory factor I (IRF-1) and downstream inflammatory mediators including the chemokine IP-10, and Nox2 (Miotto et al, 2001), (Rosenbaum et al, 2009).…”