Increased expression of the interleukin-10 gene by alveolar macrophages in interstitial lung disease

Abstract

Idiopathic pulmonary fibrosis (IPF) and bronchiolitis obliterans with organizing pneumonia (BOOP) are interstitial lung diseases of unknown pathogenesis. Alveolar macrophages play a major role in the regulation of the inflammatory response in these diseases through their ability to produce cytokines that modify the inflammatory response. Tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) exhibit proinflammatory and anti-inflammatory actions, respectively, and thus an imbalance in the expression of these cytokines may contribute to the pathogenesis of IPF and BOOP. Therefore, we quantified IL-10 and TNF-alpha mRNA levels in alveolar macrophages obtained by bronchoalveolar lavage (BAL) from patients with IPF and BOOP and in normal healthy volunteers. The level of TNF-alpha mRNA in macrophages obtained from IPF and BOOP patients was not significantly different from normal healthy subjects. However, macrophages from patients with IPF and BOOP expressed increased levels of IL-10 mRNA compared with healthy controls. In addition, stimulation of alveolar macrophages with lipopolysaccharide in the presence of a neutralizing anti-IL-10 antibody augmented the production of TNF-alpha over that seen in the absence of anti-IL-10 antibody, suggesting that the increased expression of IL-10 by alveolar macrophages may act to control the expression of TNF-alpha. Paradoxically, measurement of IL-10 protein in cell-free BAL fluid revealed lower amounts of the protein in patients with IPF and BOOP compared with healthy controls.

Increased Cell Surface Fas Expression Is Necessary and Sufficient To Sensitize Lung Fibroblasts to Fas Ligation-Induced Apoptosis: Implications for Fibroblast Accumulation in Idiopathic Pulmonary Fibrosis

“…Taken together, these findings suggest that fibroblast and myofibroblast accumulation in the lungs of IPF patients could occur as a result of impaired sensitization to Fas-induced apoptosis. They are also consistent with the developing notion that fibrosis can progress in the absence of a robust inflammatory response associated with reduced levels of proinflammatory sensitizing molecules such as TNF-a, IFN-g, and PGE 2 (1,(24)(25)(26).…”

Analysis of an IL-10 polymorphism in idiopathic pulmonary fibrosis

“…In the normal human lung, AMs constitutively produce low levels of IL-10 in their role as mediators of the host defence response, and this protein is upregulated by both LPS stimulation and TNF-a. The relation between IL-10 and TNF-a has been extensively investigated in numerous inflammatory disorders including IPF, where several studies have shown increased TNF-a in IPF despite evidence suggesting that IL-10 is also increased in these patients 6,7 (Freeburn R, Millar A, unpublished data). In a previous study we showed using semiquantitative PCR that expression of IL-10 mRNA was significantly increased in AMs from patients with IPF compared to controls.…”

“…4 In the normal lung, IL-10 is constitutively produced at a low level representing an endogenous feedback factor for the control of the inflammatory response. 5 The aetiology of IPF is unknown, but AMs from these patients exhibit elevated levels of TNF-a relative to IL-10, suggesting that in this disease the normal homeostatic mechanisms fail to regulate the TNF-a inflammatory response 6,7 (Freeburn R, Millar A, unpublished results). Differences in lipopolysaccharide (LPS)-induced IL-10 secretion have been related to corresponding differences in mRNA production implicating transcription as the principal mechanism in variable IL-10 production.…”

Structure and function of interleukin-22 and other members of the interleukin-10 family

“…These important immunological activities are implicated in several human diseases such as psoriasis [15][16][17], rheumatoid arthritis [18][19][20], and inflammatory lung and bowel diseases [21,22]. In this context, the study of IL-10 members, their interaction with receptors, and elicited cell signaling cascade, are important to understand the basis of both immunoregulation and associated diseases, establishing strategies to modulate or to control these health conditions and illnesses.…”