Macrophage migration inhibitory factor is essential for allergic asthma but not for Th2 differentiation

Abstract

Macrophage migration inhibitory factor (MIF) is increased in asthmatic patients and plays a critical role in the pathogenesis of asthma. We show here that mice lacking MIF failed to develop airway hyper-responsiveness (AHR), tissue eosinophilia, and mucus metaplasia. Analysis of the bronchoalveolar fluids revealed a substantial reduction of IL-13, eotaxin and cysteinyl-leukotrienes. The lack of these cardinal features of asthma in MIF -/-mice occurs regardless of high concentrations of IL-4 in the lung and OVAspecific IgE in the serum. Antigen-specific lymphocyte proliferation and IL-13 production were similarly increased in the draining lymph nodes of OVA-immunized and challenged MIF -/-mice compared to WT, but were reduced in the spleen of MIF -/-, thus indicating differential roles of MIF in these compartments. Stimulation of naive CD4 + cells with anti-CD3 antibody demonstrated that MIF -/-cells produced increased amounts of IFN-c and IL-4 compared to WT CD4 + cells. Finally, treatment of sensitized BALB/c mice with neutralizing anti-MIF antibody abrogated the development of ARH and airway inflammation without affecting the production of Th2 cytokines or IgE. The present study demonstrates that MIF is required for allergic inflammation, adding important elements to our knowledge of asthma pathogenesis and suggesting that neutralization of MIF might be of therapeutic value in asthma. IntroductionAllergic asthma is a disorder characterized by chronic lung inflammation, reversible airway obstruction and increases in airway hyper-responsiveness (AHR) to nonspecific stimuli. Several studies have provided compelling evidences that the lung infiltrating leukocytes and the proinflammatory mediators they produce initiate cellular damage, amplify the immune response, cause airway physiological changes and tissue remodeling [1]. The airway inflammation of asthma has a predominance of Th2 CD4 + lymphocytes, eosinophils and mast cells infiltrating the lung interstitium. Several studies indicate the existence of a mechanism dependent on IL-5 and eosinophils that induce pulmonary damage and intensify AHR [3][4][5]. In other studies, however, the induction of AHR was observed despite the absence of infiltrating eosinophils, suggesting dissociation between these phenomena [6][7][8][9][10]. Macrophage migration inhibitory factor (MIF) is a pleiotropic molecule and critical mediator of innate and acquired immune responses [11,12]. Pre-formed MIF protein is present in many cell types and is released in response to different stimuli, such as infection and cytokine stimulation [12]. MIF exhibits several proinflammatory functions, including the induction of TNF-a, IL-1 and NO release from macrophages, and the production of arachidonic acid and eicosanoids through the induction of phospholipase A 2 and cyclooxygenase [13,14]. A unique property of MIF is its secretion by immune cells in response to physiological increase in glucocorticoid levels. Once released, MIF can counterregulate the anti-inflammatory effects of steroids on cyt...

Thioredoxin suppresses airway inflammation independently of systemic Th1/Th2 immune modulation

“…Consistent with this data, MIF levels were significantly lower in colonic tissue and sera in TRX-Tg mice in a mouse model of acute DSS-induced colitis [32]. Recent studies indicate that MIF plays an essential role in the pathogenesis of allergic airway inflammation [3][4][5][6]. Upon allergen sensitization and challenge, mice lacking MIF exhibit reduced AHR, tissue eosinophilia, and mucus metaplasia with concomitant decreases in levels of eotaxin and IL-13 in BALF.…”

“…Upon allergen sensitization and challenge, mice lacking MIF exhibit reduced AHR, tissue eosinophilia, and mucus metaplasia with concomitant decreases in levels of eotaxin and IL-13 in BALF. Interestingly, the lack of these cardinal features of asthma in MIF-deficient mice occurs without affecting systemic Th1/Th2 immunity [4], which is the perfect mirror image of those seen in TRX-Tg mice. It seems likely that MIF acts as an upstream regulator for the local production of IL-13 and eotaxin in the lung, which contribute to the pathogenesis of asthma.…”

“…Recent studies suggest that MIF may play a key role in the pathogenesis of airway inflammation [3][4][5][6]. Therefore, we next examined the lungs of TRX-Tg and WT mice for differences in MIF expression in our model of asthma.…”

“…Although eosinophils are the predominant cell type in the lung of asthmatic subjects that mediate tissue damage, allergen specific Th2 cells generated in the secondary lymphoid organs and migrated into the lung are central to the pathogenesis of asthma via secretion of IL-4 and IL-5 contributing to mobilization of eosinophils and IL-9 and IL-13 contributing to AHR [2]. Additionally, recent studies have implicated MIF produced by lung epithelial cells, macrophages, and mast cells as an essential factor in the pathogenesis of asthma [3][4][5][6].…”

CD4 cell-secreted, posttranslationally modified cytokine GIF suppresses Th2 responses by inhibiting the initiation of IL-4 production

“…A ''neutralizing'' anti-GIF inhibited proliferation of purified T cells induced by anti-CD3, suggesting that GIF augments T cell activation (15). However, there was no impairment in antigen-dependent proliferation of GIF-deficient T cells (16). Moreover, the latter study demonstrated that CD4 cells purified from GIF-deficient mice secreted higher amounts of IL-4 and IFN-␥ than wild-type cells, suggesting that this cytokine inhibits the differentiation of naïve CD4 cells toward Th effectors.…”