IL-4 Signaling Mechanisms in Inflammatory Bowel Disease Mononuclear Phagocytes

: In inflammatory bowel disease (IBD), intestinal mononuclear cells secrete increased amounts of proinflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), as well as nonspecific effector molecules (i.e., superoxide anions) in vitro and in vivo. Interleukin-4 (IL-4) is an important contrainflammatory cytokine to limit monocyte and macrophage activation. Data obtained with peripheral 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 superoxide anions, respectively. We investigated molecular events involved in IL-4-induced signal transduction and regulation in IBD mononuclear phagocytes. Peripheral blood mononuclear cells were isolated by densitygradient centrifugation, intestinal lamina propria mononuclear cells 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 specific induction of signal transducer and activator of transcription 6 (Stat 6). Downregulation of TNF-α and IL-1β mRNA levels, respectively, in IBD mononuclear phagocytes is impaired in comparison with normal cells. However, no differences between IBD and normal control mononuclear phagocytes were seen in IL-4 receptor surface expression and signal transduction by IL-4induced generation of Stat 6. Impaired downregulation of TNF-α and IL-1β secretion by IL-4 in IBD mononuclear phagocytes is also seen on the mRNA level. The mechanism of IL-4 resistance may be located in elements of IL-4 receptor signal transduction downstream of Stat 6.