Pathogenesis of irritable bowel syndrome: The mast cell connection

Irritable bowel syndrome (IBS) is a highly prevalent disorder in developed countries and affects a heterogeneous group of patients suffering from chronic and recurrent abdominal pain usually associated with visceral hypersensitivity and sometimes mucosal inflammation [1]. Clearly, there is a paucity of efficacious therapeutic agents and thus poor healthrelated quality of life is frequent in many patients [2]. Although enormous progress in the understanding of IBS pathogenesis has been made implicating psychological factors, food hypersensitivity and gastrointestinal infections, it is still poorly understood [3 /7]. This review focuses on the role of mast cells in IBS with particular emphasis on bridging experimental data on laboratory animals with pathological, clinical and epidemiological data on IBS patients. Human and rodent mast cells derive from pluripotential CD34 hematopoietic progenitor cells in bone marrow, where they initiate their maturation process [8]. They then circulate as committed progenitors (c-kit , CD34 , CD13 , FcoRI ) and migrate to peripheral tissues, a process regulated by c-kit and stem cell factor [9]. At peripheral tissues, mast cells are commonly found adjacent to blood or lymphatic vessels and nerves and in close proximity to mucosal surfaces in the skin, gastrointestinal, genitourinary and respiratory tracts, where they are strategically poised for optimal interaction with the local microenvironment [10,11]. At these locations, committed progenitors may remain as a homeostatic pool or complete their differentiation process to mature mast cells in the presence of local inflammation [12]. The wide tissue distribution of mast cells throughout the body has stimulated enormous interest in their physiological role [13,14] (Table I). Classically, mast cells have been viewed in the context of allergic and parasite inflammation and mostly as pure effector cells. However, recent and compelling evidence suggests that mast cells develop both effector and sensory functions and may be critical in a variety of pathophysiological processes (Figure 1). As sensory cells they become primed or activated by a plethora of stimuli that arise from the local microenvironment. These stimuli include immune events such as cross-linking of IgE molecules with membrane-based surface receptors (FcoRI) and activation by circulating immunoglobulin light-free chains, superallergens, monomeric IgE, complement fractions and other immunoglobulin-associated receptors [15 /17]. Activation by a vast spectrum of cytokine and chemokine signals and adhesion molecules has also been postulated or described [18]. In addition, the list of non-immune stimuli is rapidly growing and includes neuropeptides, neurotransmitters, growth factors, angiogenic molecules, ATP, as well as other physical, chemical and biological agents [10,19 /28]. A summary of these stimuli is given in Table II. Mast cell effector function is mediated through the release of multifunctional biochemical messengers contained in their cytoplasmatic granules, a process called degranulation, and achieved when receptors in target cells become activated. Mast cell mediators have been classically divided into two major groups: those that are preformed, which include biogenic amines, TNF-a, chemokines,