Enhanced Expression of Interleukin-18 and its Receptor in Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) is a major interstitial lung disease (ILD). Recently, we established a new mouse model for ILD in which daily administration of interleukin (IL)-18 with IL-2 induces lethal lung injury, suggesting that IL-18 is involved in the pathogenesis of ILD. Here, utilizing immunohistochemistry, we have analyzed IL-18 and IL-18 receptor (IL-18R) alpha expression in the lungs of 18 patients with IPF/UIP and 13 control subjects by using monoclonal anti-IL-18 antibodies and a new monoclonal antibody for IL-18Ralpha (H44). IL-18 was expressed in bronchoalveolar epithelium, alveolar macrophages, and the endothelium of small vessels in control subjects, and was abundantly expressed in the majority of pulmonary cells in patients with IPF. IL-18Ralpha was expressed in bronchoalveolar epithelium and alveolar macrophages in control subjects, and was strongly expressed in interstitial cells in patients with IPF, especially in the fibroblastic foci (FF). Interestingly, IL-18Ralpha expression was only weakly observed in areas showing established fibrosis. Semiquantitative analysis revealed that the histologic FF score was significantly correlated with the IL-18Ralpha expression level in FF lesions. Moreover, IL-18 levels in the serum and bronchoalveolar lavage fluid of patients with IPF were significantly higher than those in control subjects. Our findings suggest IL-18 and IL-18R are involved in the pathogenesis of IPF/UIP.

Interleukin-18 production and pulmonary function in COPD

“…HOSHINO and co-workers [16][17][18] have shown that IL-18 can act as a co-factor for both Th1 and Th2 cell development, and several studies have subsequently reported that IL-18 may be involved in the development of Th2-type-diseases, such as asthma [14]. The present authors have previously demonstrated that treatment with recombinant IL-18 plus IL-2 induces pulmonary inflammation and lung injury in mice [19], and IL-18 and its receptor are strongly expressed in the human lung in idiopathic pulmonary fibrosis [15]. Very recently, the present authors reported that constitutive IL-18 overproduction in the lungs of mice induces emphysema [20].…”

“…Immunohistochemical analysis was performed as reported previously [15]. Anti-human IL-18 (clone 8 (mouse immunoglobulin (Ig)G2a) and clone 1-8D (mouse IgG1)) monoclonal antibodies (mAbs) were used.…”

“…Quantitative assessment of alveolar macrophages and infiltrating mononuclear cells in the general interstitium of lung tissue Quantitative assessment of alveolar macrophages and infiltration of mononuclear cells was performed as reported previously [15]. Briefly, HE sections of lung tissues obtained from COPD patients who had undergone LVRS were viewed and, in (table 1).…”

“…Percentages of IL-18 positive cells in AMs, IMNCs, CD4+, CD8+, and CD13+ cells were previously assessed as previously reported [15]. analysed by simple regression.…”

“…Activated macrophages produce large amounts of mature IL-18 after cleavage of pro-IL-18 by caspase-1 [14]. It has been reported that low levels of pro-and mature IL-18 proteins are expressed in the lungs of healthy subjects [15]. HOSHINO and co-workers [16][17][18] have shown that IL-18 can act as a co-factor for both Th1 and Th2 cell development, and several studies have subsequently reported that IL-18 may be involved in the development of Th2-type-diseases, such as asthma [14].…”