Regulation and Function of the IL-1 Family Cytokine IL-1F9 in Human Bronchial Epithelial Cells

Abstract

The IL-1 family of cytokines, which now includes 11 members, is well known to participate in inflammation. Although the most recently recognized IL-1 family cytokines (IL-1F5-11) have been shown to be expressed in airway epithelial cells, the regulation of their expression and function in the epithelium has not been extensively studied. We investigated the regulation of IL-1F5-11 in primary normal human bronchial epithelial cells. Messenger (m)RNAs for IL-1F6 and IL-1F9, but not IL-1F5, IL-1F8 or IL-1F10, were significantly up-regulated by TNF, IL-1b, IL-17 and the Toll-like receptor (TLR)3 ligand doublestranded (ds)RNA. mRNAs for IL-1F7 and IL-1F11 (IL-33) were weakly up-regulated by some of the cytokines tested. Notably, mRNAs for IL-1F6 and IL-1F9 were synergistically enhanced by the combination of TNF/IL-17 or dsRNA/IL-17. IL-1F9 protein was detected in the supernatant following stimulation with dsRNA or a combination of dsRNA and IL-17. IL-1F6 protein was detected in the cell lysate but was not detected in the supernatant. We screened for the receptor for IL-1F9 and found that lung fibroblasts expressed this receptor. We found that IL-1F9 activated mitogen-activated protein kinases and the transcription factor NF-kB in primary normal human lung fibroblasts. IL-1F9 also stimulated the expression of the neutrophil chemokines IL-8 and CXCL3 and the Th17 chemokine CCL20 in lung fibroblasts. These results suggest that epithelial activation by TLR3 (e.g., by respiratory viral infection) and exposure to cytokines from Th17 cells (IL-17) and inflammatory cells (TNF) may amplify neutrophilic inflammation in the airway via induction of IL-1F9 and activation of fibroblasts.

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.…”

Current concepts of severe asthma

“…Studies in both mice and humans show that these cells produce large amounts of IL-5 and IL-13 in the presence of the epithelial cell-derived cytokines thymic stromal lymphopoietin (TSLP), IL-25, IL-33 (70), and prostaglandin D2 (PGD2) (71,72). The release of these cytokines is induced by proteases, which are present in various allergens (73), as well as viruses, including rhinovirus, and bacteria, such as staphylococcus, which have been associated with asthma exacerbations and chronic sinusitis (74,75). Since approximately 25% of patients with severe asthma do not display atopy (at least to known allergens), it is possible that there are other environmental triggers that induce a type 2 response without invoking a Th2 response.…”

Involvement of Toll-Like Receptor 2 and Epidermal Growth Factor Receptor Signaling in Epithelial Expression of Airway Remodeling Factors

“…Primary normal human bronchial epithelial (NHBE; Lonza, Walkersville, MD) cells, from at least three different donors, were plated in 12-well culture plates and either grown in submerged or in air-liquid interface conditions, as previously described (34). NHBE cells were deprived of hydrocortisone and growth factors from the media for 24 hours before stimulation.…”

“…Real-time RT-PCR was performed with the TaqMan method using an Applied Biosystems 7,500 sequence detection system (Life Technologies, Grand Island, NY) as described previously (34). The levels of expression of mRNA were normalized to the housekeeping gene, b-actin, and results were analyzed by quantifying the absolute amount of mRNA.…”