Transcriptional regulation of cytokine function in airway smooth muscle cells

Abstract

The immuno-modulatory properties of airway smooth muscle have become of increasing importance in our understanding of the mechanisms underlying chronic inflammation and structural remodeling of the airway wall in asthma and chronic obstructive pulmonary disease (COPD). ASM cells respond to many cytokines, growth factors and lipid mediators to produce a wide array of immuno-modulatory molecules which may in turn orchestrate and perpetuate the disease process in asthma and COPD. Despite numerous studies of the cellular effects of cytokines on cultured ASM, few have identified intracellular signaling pathways by which cytokines modulate or induce these cellular responses. In this review we provide an overview of the transcriptional mechanisms as well as intracellular signaling pathways regulating cytokine functions in ASM cells. The recent discovery of toll-like receptors in ASM cells represents a significant development in our understanding of the immuno-modulatory capabilities of ASM cells. Thus, we also review emerging evidence of the inflammatory response to toll-like receptor activation in ASM cells.

Introduction

Cytokines and chemokines play a central role in regulating inflammatory and immune responses in chronic lung diseases such as asthma and COPD. Indeed, in vivo studies using selective inhibitors as well as neutralizing antibodies against various cytokines and chemokines demonstrate their importance in antigen-induced airway inflammation (leukocyte infiltration) and hyper-responsiveness in animal models of asthma [1], [2], [3]. Studies in knock-out or transgenic mice also illustrate the importance of cytokines in the abnormal airway changes induced by allergen challenge in sensitized animals [4]. A potential site for the deleterious action of many cytokines in airways disease is the airway smooth muscle a primary effector tissue historically thought to only regulate bronchomotor tone. In human cultured ASM cells that retain physiological responsiveness, cytokines alter pro-inflammatory gene expression that in turn may play an important role in the pathogenesis of chronic inflammatory airways disease [5]. Despite numerous studies of the cellular effects of cytokines on cultured ASM, few have identified downstream signaling cascades by which cytokines modulate or induce these cellular responses. In this review we discuss the role of three major intracellular signaling pathways: Mitogen-Activated Protein Kinase (MAPK), Nuclear Factor-kappa B (NF-κB), and Janus kinases and Signal Transducers and Activators of Transcription (STATs) in regulating cytokine functions, with a particular focus on inflammatory gene expression, in regulating ASM functions.

The capacity for ASM cells to respond to numerous cytokines has revealed the extensive immune-regulatory potential of these cells. In response to cytokines such as IL-1β, TNF-α and IFN-γ, ASM cells can be induced to express a host of cell adhesion and co-stimulatory molecules that allow interactions between the ASM and inflammatory cells that infiltrate the airways. Moreover, ligation of ASM cell surface molecules such as CD40 and OX40L by their respective counter-ligands leads to activation of ASM inflammatory responses. Further advances in understanding the immune-regulatory potential of ASM have come with the discovery that cytokines also upregulate the expression of multiple toll-like receptors (TLRs) in ASM cells. These latter receptors are pattern-recognition receptors that mediate innate and adaptive immune and inflammatory responses to microbial infection, tissue injury or inflammation. Emerging evidence now suggests a role for TLRs in the development, perpetuation and exacerbation of chronic inflammatory airway disease [6]. Thus, we also discuss the potential role of TLRs in the amplification of ASM inflammatory responses.