Cysteine proteases have traditionally been viewed as lysosomal mediators of terminal protein degradation. However, recent findings refute this limited view and suggest a more expanded role for cysteine proteases in human biology. Several newly discovered members of this enzyme class are regulated proteases with limited tissue expression, which implies specific roles in cellular physiology. These roles appear to include apoptosis, MHC class II immune responses, prohormone processing, and extracellular matrix remodeling important to bone development. The ability of macrophages and other cells to mobilize elastolytic cysteine proteases to their surfaces under specialized conditions may also lead to accelerated collagen and elastin degradation at sites of inflammation in diseases such as atherosclerosis and emphysema. The development of inhibitors of specific cysteine proteases promises to provide new drugs for modifying immunity, osteoporosis, and chronic inflammation.

Cigarette smoke exposure is the major cause of chronic obstructive pulmonary disease (COPD). However, only a minority of smokers develop significant COPD, and patients with asthma or asthma-like airway hyperresponsiveness or eosinophilia experience accelerated loss of lung function after cigarette smoke exposure. Pulmonary inflammation is a characteristic feature of lungs from patients with COPD. Surprisingly, the mediators of this inflammation and their contributions to the pathogenesis and varied natural history of COPD are not well defined. Here we show that IL-13, a critical cytokine in asthma, causes emphysema with enhanced lung volumes and compliance, mucus metaplasia, and inflammation, when inducibly overexpressed in the adult murine lung. MMP-2, -9, -12, -13, and -14 and cathepsins B, S, L, H, and K were induced by IL-13 in this setting. In addition, treatment with MMP or cysteine proteinase antagonists significantly decreased the emphysema and inflammation, but not the mucus in these animals. These studies demonstrate that IL-13 is a potent stimulator of MMP and cathepsin-based proteolytic pathways in the lung. They also demonstrate that IL-13 causes emphysema via a MMP-and cathepsin-dependent mechanism(s) and highlight common mechanisms that may underlie COPD and asthma. in proteases and/or reduction in pulmonary antiproteases (1). Inflammation, characterized by increased numbers of macrophages, lymphocytes, neutrophils, and/or eosinophils is a characteristic feature of lungs from patients with COPD (1,(14)(15)(16)(17)(18)(19). However, the nature of the mediators involved in this inflammation and the ability of these mediators to generate the emphysema and mucus changes, protease/antiprotease alterations, and varied natural history of COPD have not been investigated.Because Th2-dominated inflammation underlies the pathogenesis of asthma and generates AHR and eosinophilia (20-22), we hypothesized that Th2 cytokines can also activate proteolytic pathways that could contribute to the pathogenesis of COPD. To test this hypothesis, we used an inducible overexpression transgenic modeling system to target IL-13, a Th2 cytokine that is strongly implicated in the pathogenesis of asthma and causes AHR and eosinophilia (20,23), to the adult murine lung. These studies demonstrate that IL-13 causes a phenotype that mirrors human COPD including emphysema with enhanced lung volumes and pulmonary compliance; mucus metaplasia; and macrophage-, lymphocyte-, and eosinophil-rich inflammation. They also define the MMP and cathepsin abnormalities that generate the emphysema and demonstrate the efficacy of proteolytic blockade in ameliorating this response. MethodsTransgenic mice. These experiments were undertaken with CC10-rtTA-IL-13 mice in which the Clara cell 10-kDa (CC10) protein promoter and two transgenic constructs target IL-13 to the murine lung in an externally regulatable fashion. The CC10-rtTA transgenic system and the constructs that were used have been described previously by our laboratory (24). Construct 1,...

Major histocompatibility complex (MHC) class II molecules acquire antigenic peptides after degradation of the invariant chain (Ii), an MHC class II-associated protein that otherwise blocks peptide binding. Antigen-presenting cells of mice that lack the protease cathepsin S fail to process Ii beyond a 10 kDa fragment, resulting in delayed peptide loading and accumulation of cell surface MHC class II/10 kDa Ii complexes. Although cathepsin S-deficient mice have normal numbers of B and T cells and normal IgE responses, they show markedly impaired antibody class switching to IgG2a and IgG3. These results indicate cathepsin S is a major Ii-processing enzyme in splenocytes and dendritic cells. Its role in humoral immunity critically depends on how antigens access the immune system.