Downregulation Of Proinflammatory Cytokines Research Articles

Mechanism of the beneficial effects of pentoxifylline during sepsis: maintenance of adrenomedullin responsiveness and downregulation of proinflammatory cytokines.

Although it is known that pentoxifylline (PTX) produces various beneficial effects during sepsis, it remains unknown whether this agent has any salutary effects on the depressed vascular responsiveness to adrenomedullin (ADM), a novel potent vasodilatory peptide, under such conditions. Adult male Sprague-Dawley rats were subjected to polymicrobial sepsis by cecal ligation and puncture (CLP). One hour after CLP, PTX (50 mg/kg body wt) or vehicle (normal saline) was infused intravenously over 90 min. Twenty hours after CLP (i.e., the late, hypodynamic stage of sepsis), the thoracic aorta and small intestine were isolated and preconstricted by norepinephrine. Rat ADM (10(-7) M) was applied, and the percentage of ADM-induced relaxation in the aortic rings and resistance vessels in the small intestine was determined. In addition, plasma ADM was determined by radioimmunoassay and tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1beta, and IL-6 levels were measured by enzyme-linked immunosorbent assay. The percentage of ADM-induced vascular relaxation in the aortic rings and resistance vessels of the isolated gut was significantly reduced 20 h after CLP. Administration of PTX early after the onset of sepsis, however, prevented the decrease in vascular ADM responsiveness at the macro- and microcirculatory levels. Plasma ADM levels increased after CLP, irrespective of PTX infusion, indicating that the effect of PTX was not mediated by altering ADM release. The upregulated TNF-alpha, IL-1beta, and IL-6 during late sepsis were, however, attenuated by PTX administration, suggesting that maintenance of ADM responsiveness by this agent appears to be due to downregulation of these cytokines. Since early administration of PTX maintains vascular ADM responsiveness even during the late stage of sepsis, this agent appears to be a useful adjunct in preventing the deterioration in hemodynamics and cardiovascular function during the progression of polymicrobial sepsis.

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.