Elsevier

Cytokine

Volume 99, November 2017, Pages 114-123
Cytokine

IL-36 induces cytokine IL-6 and chemokine CXCL8 expression in human lung tissue cells: Implications for pulmonary inflammatory responses

https://doi.org/10.1016/j.cyto.2017.08.022Get rights and content

Highlights

Abstract

IL-36α, IL-36β and IL-36γ are cytokine members of IL-1 family. Although IL-36 expression was observed in human lung during pulmonary infections, it remains unknown whether IL-36 could act directly on lung tissue cells during pulmonary inflammatory responses. In this study, we showed that IL-36 receptor was expressed in human lung fibroblasts and bronchial epithelial cells. Correspondingly, IL-36α, IL-36β or IL-36γ up-regulated gene expression of cytokine IL-6 and chemokine CXCL8 in human lung fibroblasts and bronchial epithelial cells, and promoted IL-6 and CXCL8 release from human lung fibroblasts and bronchial epithelial cells. The production of IL-6 and CXCL8 in these lung tissues cells induced by IL-36α, IL-36β or IL-36γ was regulated by p38MAPK, ERK or Akt signaling pathways. Taken together, the above results suggest that IL-36–mediated IL-6 and CXCL8 production in human lung fibroblasts and bronchial epithelial cells may be involved in pulmonary inflammation especially caused by bacterial or viral infections.

Introduction

IL-36 is a set of cytokines in the IL-1 family, which includes three agonists, IL-36α, IL-36β and IL-36γ, and an IL-36 receptor antagonist (IL-36Ra) [1]. IL-36α, IL-36β and IL-36γ signal through a heterodimeric receptor (IL-36R and IL-1RAcP), resulting in the activation of various intracellular signaling pathways [1], [2]. IL-36 receptor is expressed by a variety of cell types, including keratinocytes, dendritic cells (DCs), monocytes and CD4+T cells [2], [3], [4]. IL-36 has strong stimulatory effects on DCs and CD4+T cells, and it regulates Th1 and Th17 responses induced by Aspergillus fumigatus [5]. Besides, IL-36 could promote a strong pro-inflammatory signature in keratinocytes [6]. Therefore, IL-36 cytokines contribute to inflammatory reactions.

Indeed, both IL-36 and IL-36R are expressed in skin, lung and gut [1], [7]. IL-36 cytokines can be induced in monocytes/macrophages, T cells, keratinocytes and other epithelial cell types upon the stimulation of different agents, including cytokines, bacteria, virus, or other pathologic conditions [1], [8], [9]. It has been reported increased IL-36γ levels in plasma and bronchoalveolar lavage fluids of patients with acute respiratory distress syndrome because of pneumonia [10]. A recent study demonstrated that influenza virus induced IL-36α production from alveolar epithelial cells during influenza pneumonia [11]. Besides, IL-36α, IL-36β and IL-36γ expression could be up-regulated in human bronchial epithelial cells upon the stimulation of cigarette smoke condensate [12], [13]. Increased IL-36γ mRNA expression was also observed in biopsies of recurrent respiratory papillomas, and IL-36γ mRNA expression levels were associated with its disease severity [14]. Furthermore, genetic mapping of loci involved in allergen-induced airway hyperresponsiveness has characterized the genomic region containing IL-36α, IL-36β and IL-36γ, and IL-36Ra genes in mice[15], and IL-36γ expression levels in asthma-susceptible A/J mice were higher than those of resistant C3H/HeJ mice [16], [17]. Taken together, these studies suggest the pathophysiological relevance of IL-36/IL-36R axis to pulmonary inflammatory responses.

Lung tissue cells, including epithelial cells and fibroblasts, play a major role in initiating, amplifying and maintaining pulmonary inflammatory responses by expressing cytokines, chemokines and other inflammatory mediators in a paracrine or autocrine manner [18], [19], [20], [21]. However, IL-36-mediated activation of lung tissue cells remains unknown. We therefore designed this work to characterize the activation effects of IL-36α, IL-36β and IL-36γ on human lung fibroblasts and bronchial epithelial cells. We examined the expression of cytokines and chemokines and the modulation of intracellular signaling molecules on the regulation of the induction of cytokines and chemokines from human lung fibroblasts and bronchial epithelial cells stimulated by IL-36 cytokines.

Section snippets

Reagents

Recombinant human IL-36α, IL-36β, IL-36γ or IL-36Ra were purchased from R&D Systems. Mouse anti-extracellular signal-regulated kinase (ERK), anti-phospho-p38 mitogen-activated protein kinase (MAPK), and anti-Akt monoclonal antibodies were from Cell Signaling Technology Corp (Beverly, MA). IκB-α phosphorylation inhibitor BAY11-7082, ERK inhibitor U0126, Jun N-terminal kinase (JNK) inhibitor SP600125, p38MAPK inhibitor SB203580, phosphatidylinositol 3-OH kinase (PI3K)/Akt inhibitor LY294002 and

HLF and HBEC expressed IL-36 receptor

A recent study has demonstrated that human monocytes expressed IL-36 receptor [2]. We therefore used human monocytes as a positive control to examine whether HLF and HBEC expressed IL-36 receptor by performing quantitative RT-PCR. As shown in Fig. 1, IL-36R and IL-1RAcP were readily detected in HLF and HBEC.

IL-36α, IL-36β and IL-36γ induced HLF and HBE to express cytokine IL-6 and chemokine CXCL8

Given that HLF and HBEC expressed the prerequisite receptors for IL-36, we next studied the biological function of IL-36 receptor expression in HLF and HBEC. We examined the ability of

Discussion

Pulmonary inflammatory responses result from the multipartite interactions of, at least, lung tissue cells as well as a variety of other immune cells [27]. In this scenario, human lung fibroblasts and bronchial epithelial cells are not passive and actively participate in inflammatory cascades [19], [20]. Airway epithelial cells are a major source of IL-36 cytokines in response to cytokines, infectious agents and cigarette smoke condensate [10], [12], [13]. There are several studies revealing

Acknowledgments

This study is supported by National Natural Science Foundation of China grants (Nos. 81370110 and 81572038 to J.C.), Chongqing Science and Technology Commission Grant for Distinguished Young Scholars of Chongqing (cstc2014jcyjjq10002 to J.C.), The Youth Top-notch Support Plan of Chongqing Program to J.C., Training Program of the Research grant of Chongqing Medical University (No. 201409 to J.C.).

Conflicts of interests

The authors declare that there is no conflict of interests regarding the

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