IL-4 SIGNALING MECHANISMS IN INFLAMMATORY BOWEL-DISEASE MONONUCLEAR PHAGOCYTES

In inflammatory bowel disease (IBD), intestinal mononuclear cells secr ete increased amounts of proinflammatory cytokines interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), as well as nonsp ecific effector molecules (i.e., superoxide anions) in vitro and in vi vo. Interleukin-4 (IL-4) is an important contrainflammatory cytokine t o limit monocyte and macrophage activation. Data obtained with periphe ral monocytes indicate that IL-4-mediated downregulation of activation may be impaired in IBD. High IL-4 concentrations are able to overcome the impairment in downregulation of proinflammatory cytokines and sup eroxide anions, respectively. We investigated molecular events involve d in IL-4-induced signal transduction adn regulation in IBD mononuclea r phagocytes. Peripheral blood mononuclear cells were isolated by dens ity-gradient centrifugation, intestinal lamina propria mononuclear cel ls by collagenase digestion. Proinflammatory cytokine mRNA levels were assessed by semiquantitative polymerase chain reaction using internal standards. IL-4 receptor expression was investigated by radiolabeled ligand binding studies and IL-4 receptor signal transduction by specif ic induction of signal transducer and activator of transcription 6 (St at 6). Downregulation of TNF-alpha and IL-1 beta mRNA levels, respecti vely, in IBD mononuclear phagocytes is also seen on the mRNA level. Th e mechanism of IL-4 resistance may be located in elements of IL-4 rece ptor signal transduction downstream of Stat 6.