Systemic consequences of intestinal inflammation

A large number of changes, distant from the intestinal mucosa and involving many organ systems, may accompany the inflammatory process in ulcerative cohtis (UC) or Crohn's disease (CD). The systemic response to inflammation includes changes in the concentration of many plasma proteins, known as the acute-phase proteins, and several neuroendocrine, metabolic, and hematopoietic alterations collectively termed the acute-phase response [1]. The acute-phase response occurs in many clinical situations characterized by tissue injury, such as trauma, ischemia, burns, infections, malignancy, and autoimmune diseases. At the molecular level these symptoms correlate with changes in the levels of proinflammatory cytokines such as tumor necrosis factor (TNF), interleukin (IL)-l, and IL-6, although other cytokines and chemokines also mediate the acute phase response. Many constitutional symptoms such as anorexia, malaise, fatigue, fever, myalgias, arthralgias, night sweats, weight loss and cachexia are directly or indirectly attributed to the effects of these proinflammatory cytokines. During inflammation the inflammatory cytokines TNF, IL-1 and IL-6 are secreted in that order [2, 3]. Although many cytokine effects are predominantly paracrine and autocrine, they do mediate systemic effects [4]. For example, central infusion of TNF led to predominant anorexia whereas peripheral production of TNF produced predominant metabolic losses of protein [5, 6]. TNF is a 17 kDa protein that is produced by cells of hematopoietic lineage in response to several stimuli such as bacterial pathogens and lipopolysaccharide. It is first produced as a maebrane-bound protein of 26 kDa, which is cleaved to the mature form by the TNF-α converting enzyme. It has several biological effects depending on the amount and the rapidity with which it is produced in response to a specific stimulus. High levels of TNF that are produced acutely lead to shock and tissue injury, vascular leakage syndrome, acute respiratory distress syndrome (ARDS), gastrointestinal necrosis, acute tubular necrosis, adrenal hemorrhage, disseminated intravascular coagulation, and fever. Chronic low-dose exposure to TNF leads to weight loss, anorexia, protein catabolism, lipid depletion, hepatosplenomegaly, insulin resistance, acute-phase protein release, and endothelial activation [6-8]. IL-1 is a family of three proteins, IL-1α, IL-1 β, and the IL-1 receptor antagonist (IL-lra); the latter acts as inhibitor of IL-1 signaling [9,10]. IL-1 α and IL-1β are synthesized as precusors and are cleaved to the mature forms by the action of interleukin-1β-converting enzyme (ICE) (caspase-1). IL-1 function as a lymphocyte-activating factor by enhancing the production of IL-2, and IL-2 receptors by T lymphocytes. It synergizes with various colony-stimulating factors to stimulate early bone marrow hematopoietic progenitor cell proliferation. IL-1 and TNF share numerous biologic activities and frequently act in synergism. IL-1 stimulates the catabolism of muscle, and in joints stimulates synovial cell proHferation, cartilage and bone resorption, and collagen deposition. The effects of IL-1 on muscles and joints contribute to the myalgias and arthralgias associated with illness. Many of the proinflammatory activities of IL-1 relate to the generation of small mediator molecules, frequently in synergy with TNF, such as platelet-activating factor and leukotrienes, prostanoids, nitric oxide, and chemokines. IL-1 has several proinflammatory activities, such as induction of fever, slow-wave sleep, anorexia, and neuropeptide release. Hypotension, myocardial suppression, septic shock, and death can all be physiologic responses to overwhelming expression of IL-1 and other proinflammatory cytokines [11]. Humans injected with IL-1 experience fever, headache, myalgias, and arthralgias, each of which is reduced by the coadministration of COX inhibitors [12]. IL-6 is a 26-kDa protein produced by a wide variety of cells. IL-6 is one of the principal mediators of the clinical manifestations of tissue injury, including fever, cachexia, leukocytosis, thrombocytosis, increased plasma levels of acute-phase proteins, and decreased plasma levels of albumin. It is a pleiotropic cytokine with both proinflammatory and antiinflammatory properties. IL-6 also stimulates plasmacytosis and hypergammaglobulinemia and activates the hypothalamic- pituitary-adrenal axis [2]. In addition to differentiating B cells, IL-6 stimulates proliferation of thymic and peripheral T cells. Along with IL-1, IL-6 induces T cell diff'erentiation to cytolytic T cells and activates natural killer cells. These observations emphasize the importance of IL-6 in both innate and adaptive immunity. In addition to its immunologic/inflammatory role, IL- 6 may play an important role in bone metabolism, spermatogenesis, epidermal proliferation, megakaryocytopoiesis, and neural cell differentiation and proliferation. The age-associated rise in IL-6 has been linked to lymphoproliferative disorders, multiple myeloma, osteoporosis, and Alzheimer's disease [13]. Recently IL-6/IL-6 receptor (IL.6R) signaling has been shown to be crucial in liver regeneration following hepatectomy [14, 15]. The IL-6 family of cytokines, apart from IL-6 itself, comprises IL-11, ciliary neurotrophic factor, cardiotropin, oncostatin M, leukemia inhibitory factor, and neurotrophin 1 /B cell stimulating factor 3, which all share the common signal transducer gpl30 as part of their receptors [15]. Elevated mucosal and serum levels of several proinflammatory cytokines have been observed in patients with CD and UC, including IL-1 and TNF. IL-6 serum levels have been reported to be elevated in active CD but not in UC, whereas elevated circulating levels of IL-6R have been detected in active stages of both diseases [16]. Increased serum levels of IL-8 have also been reported in active UC but not in CD [17]. Approximately 90% of patients with CD have a triad of features that are persistent and progressive, namely diarrhea, abdominal pain, and weight loss [18]. As many as 40% of patients with UC may experience noticeable weight loss [19]. Cachexia, the loss of body mass that occurs in severe chronic inflammatory disease, results from decreases in skeletal muscle, fat tissue, and bone mass [20]. Cytokines such as IL-1, IL-6, TNF, and interferon gamma (IFN-y) contribute to these processes [21]. Investigators have found a link between inflammatory cytokines and muscle damage. TNF-α and IFN-γ are both activators of nuclear factor kappa B (NF-κB) in muscle. Activation of N F - ^kappa;B results in the decreased expression of MyoD, a transcription factor that is essential for repair of damaged skeletal muscle. Thus, the net effect of TNF-α and IFN-γ is defective muscle repair which may explain the cachexia that develops in patients with cancer and other high TNF-α states. Although cachexia is characterized by hypermetabolism, defined as an elevation in resting energy expenditure, in CD patients without malabsorption, short-term weight change is more closely related to decreased caloric intake rather than to increased resting energy expenditure. Although 'sitophobia' - in anticipation of abdominal pain - may contribute to weight loss, it usually relates to the severity of anorexia. Anorexia is one of the most common symptoms associated with acute illness, results from proinflammatory cytokine activity and has both central and peripheral elements [4]. Several cytokines affect food intake directly or indirectly with effects on other mediators such as corticotrophin- releasing hormone, serotonin, cholecystokinin, neuropeptide Y, insulin or leptin. A number of hypothalamic nuclei involved in eating behavior contain binding sites for cytokines [22]. In animals endotoxin increases the plasma levels of leptin and white fat leptin mRN A suggesting that leptin may be a mediator of anorexia in inflammatory states [4, 23]. Several alterations in gastrointestinal function that indirectly affect nutritional status have been ascribed to proinflammatory cytokines, including altered gastric emptying, decreases in intestinal blood flow, changes in small bowel motility and cellular proliferation, and altered ion fluxes [4]. A significant percentage of patients with active CD and UC hawQ fever, usually low-grade [19, 24]. Several cytokines, including IL-1α, IL-1β, TNF, lymphotoxin α (LT-α), IFN-α and IL-6, are intrinsically pyrogenic in that they produce a rapid-onset fever by acting directly on the hypothalamus without the requirement for the formation of another cytokine. Several other cytokines that use the gpl30 signal transducer as part of their receptor, as mentioned earlier, may also contribute to the febrile response [25]. Pyrogenic cytokines released during the inflammatory response interact with a rich vascular network close to the cluster of neurons in the preoptic/anterior hypothalamus. These sites, called the circumventricular organs or organum vasculosum laminae terminalis (OVLT), possess little if any blood-brain barrier. It is likely that endothelial cells lining the OVLT either offer no resistance to the movement of pyrogenic cytokines into the brain or release arachidonic acid metabolites which then may diffuse into the preoptic/anterior hypothalamic region to induce fever. Alternatively, prostaglandin E2 (PGE₂) and other prostaglandins may be produced by the endothelial cells which, in turn, induce a neurotransmitter-like substance, such as cAMP, that acts to raise the set-point [25].