The Pivotal Role of Signal Regulatory Protein α in Exacerbating Pulmonary Fibrosis Complicated with Bacterial Infection

The pathogenesis of pulmonary fibrosis remains unknown. However, bacterial infections in patients with idiopathic pulmonary fibrosis are a serious complication that exacerbate the disease. Serum levels of Surfactant Protein D (SPD) are known to be elevated in patients with pulmonary fibrosis, but the role of SPD in pulmonary fibrosis complicated with bacterial infection is unknown. Lipopolysaccharide upregulates Interleukin (IL)-12p40 expression and IL-12p40 promotes Interferon Gamma (IFNγ) production to induce the T helper cell 1 (Th1) immune response via Signal Transducers and Activators of Transcription 4 (STAT4) signaling. A lack of IFNγ shifts the immune response from Th1 to Th2. IL-4 is a profibrotic Th2 cytokine that activates fibroblasts. Granulocyte-macrophage colony-stimulating factor induced by IL-1 and TNFα during the Th1 immune response upregulates Signal Regulatory Protein α (SIRPα) expression. Interferon Regulatory Factor 1 (IRF1) functions as the promoter activator of IL-12p40 after stimulation with LPS. SPD is a ligand for SIRPα, and SPD/SIRPα ligation activates the Mitogen-Activated Protein Kinase (MAPK)/Extracellular Signal-Related Kinase (ERK) signal cascade; ERK downregulates Interferon Regulatory Factor 1 (IRF1) expression. Consequently, the SPD/SIRPα signaling pathway decreases IL-12p40 production in human macrophages after exposure to LPS. IL-12p40 is a key immunoregulatory factor in bacterial infection that promotes production of IFNγ by T lymphocytes. Pulmonary fibroblasts are activated by IL-4/IL-4R ligation. IFNγ induces IRF1 via STAT1 signaling, and IRF1 acts as the promoter repressor of IL-4 to attenuate its production. IFNγ also inhibits IL-4R expression. A reduction in IFNγ induced by IL-12p40 deficiency via the SPD/SIRPα signaling pathway enhances IL-4 and IL-4R expression to augment the activity of fibroblasts. This finding indicates that pulmonary fibrosis is exacerbated by SPD/SIRPα signaling during bacterial infection.

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Interferon Regulatory Factor-1 in Flagellin-Induced Reprogramming: Potential Protective Role of CXCL10 in Cornea Innate Defense AgainstPseudomonas aeruginosaInfection

Investigative Opthalmology & Visual Science ◽

10.1167/iovs.13-12453 ◽

2013 ◽

Vol 54 (12) ◽

pp. 7510 ◽

Cited By ~ 18

Author(s):

Gi Sang Yoon ◽

Chen Dong ◽

Nan Gao ◽

Ashok Kumar ◽

Theodore J. Standiford ◽

...

Keyword(s):

Interferon Regulatory Factor ◽

Protective Role ◽

Regulatory Factor ◽

Innate Defense ◽

Interferon Regulatory Factor 1

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The role of interferon regulatory factor-1 and interferon regulatory factor-2 in the interferon gamma mediated growth inhibition of human breast carcinoma cell lines

Journal of the American College of Surgeons ◽

10.1016/s1072-7515(00)00582-2 ◽

2000 ◽

Vol 191 (4) ◽

pp. S67

Author(s):

Steven R Hunt ◽

John H Yim ◽

Susan Wu ◽

Gerard M Doherty

Keyword(s):

Breast Carcinoma ◽

Interferon Gamma ◽

Carcinoma Cell ◽

Interferon Regulatory Factor ◽

Human Breast ◽

Regulatory Factor ◽

Carcinoma Cell Lines ◽

Interferon Regulatory Factor 1 ◽

Breast Carcinoma Cell Lines

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Pulmonary Inflammation Induced by Pseudomonas aeruginosa Lipopolysaccharide, Phospholipase C, and Exotoxin A: Role of Interferon Regulatory Factor 1

Infection and Immunity ◽

10.1128/iai.70.3.1352-1358.2002 ◽

2002 ◽

Vol 70 (3) ◽

pp. 1352-1358 ◽

Cited By ~ 49

Author(s):

Catharina W. Wieland ◽

Britta Siegmund ◽

Giorgio Senaldi ◽

Michael L. Vasil ◽

Charles A. Dinarello ◽

...

Keyword(s):

Pseudomonas Aeruginosa ◽

Pulmonary Inflammation ◽

Interferon Regulatory Factor ◽

Cell Infiltration ◽

Exotoxin A ◽

Regulatory Factor ◽

Interferon Regulatory Factor 1 ◽

Tnf Α ◽

Ifn Γ

ABSTRACT Chronic pulmonary infection with Pseudomonas aeruginosa is common in cystic fibrosis (CF) patients. P. aeruginosa lipopolysaccharide (LPS), phosholipase C (PLC), and exotoxin A (ETA) were evaluated for their ability to induce pulmonary inflammation in mice following intranasal inoculation. Both LPS and PLC induced high levels of tumor necrosis factor alpha (TNF-α), interleukin 1β (IL-1β), IL-6, gamma interferon (IFN-γ), MIP-1α and MIP-2 in the lungs but did not affect IL-18 levels. ETA did not induce TNF-α and was a weak inducer of IL-1β, IL-6, macrophage inflammatory protein 1α (MIP-1α), and MIP-2. Remarkably, ETA reduced constitutive lung IL-18 levels. LPS was the only factor inducing IFN-γ. LPS, PLC, and ETA all induced cell infiltration in the lungs. The role of interferon regulatory factor-1 (IRF-1) in pulmonary inflammation induced by LPS, PLC, and ETA was evaluated. When inoculated with LPS, IRF-1 gene knockout (IRF-1 KO) mice produced lower levels of TNF-α, IL-1β, and IFN-γ than did wild-type (WT) mice. Similarly, a milder effect of ETA on IL-1β and IL-18 was observed for IRF-1 KO than for WT mice. In contrast, the cytokine response to PLC did not differ between WT and IRF-1 KO mice. Accordingly, LPS and ETA, but not PLC, induced expression of IRF-1 mRNA. IRF-1 deficiency had no effect on MIP-1α and MIP-2 levels and on cell infiltration induced by LPS, PLC, or ETA. Flow cytometric evaluation of lung mononuclear cells revealed strongly reduced percentages of CD8+ and NK cells in IRF-1 KO mice compared to percentages observed for WT mice. These data indicate that different virulence factors from P. aeruginosa induce pulmonary inflammation in vivo and that IRF-1 is involved in some of the cytokine responses to LPS and ETA.

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