Interleukin-1 Family Member 9 Stimulates Chemokine Production and Neutrophil Influx in Mouse Lungs

Abstract

Interleukin-1 (IL-1) is a proinflammatory cytokine that signals through the Type I IL-1 receptor (IL-1RI). Novel IL-1-like cytokines were recently identified. Their functions in lung disease remain unclear. Interleukin-1 family member-9 (IL-1F9) is one such IL-1-like cytokine, expressed in the lungs of humans and mice. IL-1F9 signals through IL-1 receptor-related protein 2 (IL-1Rrp2/IL-1RL2), which is distinct from IL-1RI. We sought to determine if IL-1F9 acts as a proinflammatory cytokine in lung disease. IL-1F9 protein was increased in lung homogenates of house dust mite-challenged A/J mice compared with controls, and expression was seen in airway epithelial cells. The intratracheal administration of recombinant mouse IL-1F9 increased airway hyperresponsiveness and induced neutrophil influx and mucus production, but not eosinophilic infiltration in the lungs of mice. In addition, IL-1a protein levels in bronchoalveolar lavage fluid, chemokines, and chemokine-receptor mRNA expression in the lungs were increased after the instillation of intratracheal IL-1F9. Consistent with these changes, NF-kB transcription factor activity was increased in the lungs of mice challenged with IL-1F9 and in a macrophage cell line treated with IL-1F9. These data suggest that IL-1F9 is upregulated during inflammation, and acts as a proinflammatory cytokine in the lungs.

Alarmin Function of Cathelicidin Antimicrobial Peptide LL37 through IL-36γ Induction in Human Epidermal Keratinocytes

“…and CCL20, and cytokines IL-6, G-CSF, and GM-CSF, which can recruit and activate DC, macrophages, neutrophils, T cells, and NK cells. Studies in other epithelial tissues, such as human bronchial epithelial cells and mouse lungs, showed that IL-36, particularly IL-36g, induces the neutrophil-attracting chemokines IL-8 and CXCL1, the T cell-attracting chemokines CXCL10, and the DC-attracting and Th17-attracting chemokine CCL20, as well as cytokines and growth factors, including IL-6, G-CSF, and GM-CSF (35,36). Data from previous studies combined with our data indicate that IL-36g would activate epithelial cells to induce chemokines and recruit inflammatory cells for the initial stages of innate immunity in skin inflammation.…”

Deoxycholic acid inhibited proliferation and induced apoptosis and necrosis by regulating the activity of transcription factors in rat pancreatic acinar cell line AR42J

“…DNA-binding activity assays for 40 TFs in nuclear proteins were determined using Panomics Procarta Transcription Factor Assay Kit (40-plex Panel 1; Affymetrix, Santa Clara, CA) based on Luminex xMAP technology as previous study (Jiang et al 2006;Ramadas et al 2011). Briefly, nuclear protein was incubated with a mixture of biotin-labeled cis-element probes to form protein/DNA complexes.…”

Interleukin-36 cytokines may overcome microbial immune evasion strategies that inhibit interleukin-1 family signaling

“…These ligands included double-stranded RNA [poly(I:C)], flagellin, and Mycoplasma fermentans synthetic lipopeptide (FSL-1), LPS, and zymosan and implicate the IL-36s in immunity against bacteria, fungi, and viruses (24,79,82). Confirmatory and complementary studies using intact microorganisms have reported increased production of IL-36g in the lung and oral epithelial cells after exposure to rhinovirus, dust mites, or the bacterial pathogens Pseudomonas aeruginosa or Porphyromonas gingivalis (22,(83)(84)(85), in monocytes activated by LPS (86), and in macrophages infected with Mycobacterium tuberculosis (87). All three IL-36s can be induced in peripheral blood mononuclear cells by the opportunistic fungal pathogen Aspergillus fumigatus (88), whereas LPS and Burkholderia species of bacteria have been reported to increase the production of IL-36a in macrophages (89,90).…”

“…It is conceivable that IL-33 can act in a similar manner. Although it remains to be determined whether the IL-36s are proteolytically processed in vivo, the likelihood that they can act as full-length proteins (20)(21)(22)(23)(24)78) or may be activated by proteases other than caspase-1 (73,75,76) opens the possibility that the IL-36s are not affected by the viral immune evasion mechanisms that block the activation of the inflammasome (Fig. 4).…”

“…2A). Endogenous activation of the IL-36-IL-1RL2 pathway was first demonstrated in a human ovarian tumor cell line (21) and later confirmed in a mouse macrophage cell line (22) and several primary human cell types, including synovial fibroblasts, articular chondrocytes (23), bronchial epithelial cells (24), keratinocytes (25,26), and colonic subepithelial myofibroblasts (27). Evidence from in vitro cellular activation and gene expression analyses suggest that the three IL-36s have comparable activities (21,25,(27)(28)(29)(30)(31).…”