CCL11 blocks IL-4 and GM-CSF signaling in hematopoietic cells and hinders dendritic cell differentiation via suppressor of cytokine signaling expression.

The chemokine eotaxin/CCL11 is an important mediator of leukocyte migration, but its effect on inflammatory cytokine signaling has not been explored. In this study, we find that CCL11 induces suppressor of cytokine signaling (SOCS)1 and SOCS3 expression in murine macrophages, human monocytes, and dendritic cells (DCs). We also discover that CCL11 inhibits GM-CSF-mediated STAT5 activation and IL-4-induced STAT6 activation in a range of hematopoietic cells. This blockade of cytokine signaling by CCL11 results in reduced differentiation and endocytic ability of DCs, implicating CCL11-induced SOCS as mediators of chemotactic inflammatory control. These findings demonstrate cross-talk between chemokine and cytokine responses, suggesting that myeloid cells tracking to the inflammatory site do not differentiate in the presence of this chemokine, revealing another role for SOCS in inflammatory regulation.

Cell salvage alters the systemic inflammatory response after off-pump coronary artery bypass grafting surgery.

BACKGROUND: Retransfused cardiotomy suction blood contains elevated inflammatory markers and is a bypass independent source of inflammatory mediators. We hypothesized that, during off-pump coronary artery bypass (OPCAB) grafting surgery, avoiding retransfusion of unwashed cardiotomy suction blood would beneficially alter both urinary and plasma cytokine concentrations and be renoprotective. METHODS: Thirty-seven OPCAB surgery patients were randomly allocated to control (retransfusion of unwashed shed blood) and treatment (retransfusion of washed shed blood or discarding of unwashed blood) groups. Over 72 hours we measured plasma (tumor necrosis factor-alpha [TNF-alpha], interleukin-8, interleukin-6, interleukin-10, TNF soluble receptor-2, and interleukin-1 receptor antagonist) and urinary TNF soluble receptor-2 and interleukin-1 receptor antagonist and markers of renal injury and dysfunction (N-acetyl beta D glucosaminidase and alpha1-microglobulin). RESULTS: We demonstrated elevated proinflammatory cytokines in cardiotomy suction blood, which were effectively eliminated by cell salvage. After retransfusion, in comparison with controls, the treatment group had reduced plasma TNF soluble receptor-2. As compared with controls, treatment group patients also demonstrated significantly reduced levels of the urinary anti-inflammatory cytokine TNF soluble receptor-2. There were no between group differences in markers of renal injury or dysfunction. CONCLUSIONS: We have demonstrated that the management of shed mediastinal blood alters perioperative, systemic, plasma and urinary cytokine homeostasis at OPCAB surgery but does not impact on subclinical renal injury or dysfunction in this low risk group of patients.

Methylprednisolone increases urinary nitrate concentrations and reduces subclinical renal injury during infrarenal aortic ischemia reperfusion.

OBJECTIVE: This study tests the hypothesis that methylprednisolone may influence eNOS activity in renal arterial and venous vascular beds and impede subclinical renal injury. SUMMARY BACKGROUND DATA: Acute renal failure is a major complication of cardiovascular surgery. Renal damage arises in part from excessive vasoconstriction mediated by an imbalance of vasoconstrictive ET-1 and vasodilatory NO produced by eNOS. While methylprednisolone may reduce subclinical renal injury as measured by urinary N-acetyl-beta-D-glucosaminidase (beta-NAG), its effects upon eNOS activity in renal arterial and venous vascular beds, reflected by urinary nitrate levels, is unclear. METHODS: A porcine model of normotensive, euvolemic infrarenal aortic ischaemia-reperfusion was used. Forty-two pigs underwent a 60-minute laparotomy followed by 150 minutes of infrarenal ischemia and 180 minutes of reperfusion. Animals were randomized to receive methylprednisolone 30 mg/kg or placebo after induction of general anesthesia. Urinary beta-NAG levels were assessed as an index of subclinical renal injury, whereas urinary nitrate was assessed as an indicator of eNOS activity in renal arterial and venous vascular beds. RESULTS: Methylprednisolone treatment did not influence mean arterial, central venous, or pulmonary artery wedge pressures but suppressed plasma IL-6 levels. After the ischemia-induced rise from preanaesthetic baseline levels, urinary beta-NAG levels declined to significantly lower values in the MP group, indicative of MP renal protection (P < 0.05). Conversely, urinary nitrate levels indicative of vascular e-NOS activity remained significantly and persistently higher in MP-treated animals (P < 0.05). CONCLUSION: This study, in a porcine model of renal ischaemia-reperfusion injury, shows the benefits of methylprednisolone pretreatment in enhancing urinary nitrate levels indicative of vascular eNOS activity and the reduction of urinary beta-NAG levels, which represent subclinical renal injury.

A clinical, renal and immunological assessment of surface modifying additive treated (SMART) cardiopulmonary bypass circuits.

Biocompatible cardiopulmonary bypass (CPB) circuits aim to reduce contact activation and its physiological consequences. We investigated the hypothesis that use of Surface Modifying Additive (SMA)-treated circuits (Sorin Group Ltd) compared with non-SMA circuits would be associated with preservation of blood pressure during CPB and modulation of perioperative subclinical renal function (urinary alpha-1-microglobulin (alpha-1-m)) and plasma and urinary cytokine changes. In a study of low-risk CABG patients (n=40), randomized to SMA (n=20) versus non-SMA circuits (n=20), we found better preserved blood pressure at CPB initiation in SMA patients (p <0.05), particularly in ACE-inhibited SMA patients (n =11) versus ACE-inhibited non-SMA patients (n =10) (p <0.05). Plasma anti-inflammatory IL-10, as well as urinary alpha-1-m, were elevated 48 hours postoperatively (p <0.05). SMA patients also had lower blood loss (p <0.05). SMA circuits have some clinical benefit, especially in ACE-inhibited patients.

The effect of methylprednisolone on cytokine concentration and leukocyte adhesion molecule expression in an isolated cardiopulmonary bypass system.

This study examines the effect of methylprednisolone on cytokine balance and adhesion molecule expression within an isolated cardiopulmonary bypass (CPB) system. This isolated CPB system is an in vitro model which simulates the pro-inflammatory immune response. Whole blood from 10 volunteers was obtained in two equal amounts. Heparin and saline were added to the control group while heparin and methylprednisolone were added to the methylprednisolone group. The blood was added to two identical CPB circuits and bypass commenced by a trained perfusionist. Samples were taken at blood donation (Sample 0), 10 min after the addition of drugs (Sample 1) and after 30, 60 and 90 min of CPB (Samples 2, 3 and 4, respectively). Cytokines interleukin-8 (IL-8), interleukin-10 (IL-10), interleukin-1 receptor antagonist (IL-1ra) and tumour necrosis factor soluble receptor 2 (TNFsr2) and the leucocyte adhesion molecules L-selectin, HLA DR, CD18 and CD11b were determined. IL-8 increased in both groups. This increase was significantly less in the methylprednisolone group. Increases in granulocyte CD11b and CD18 expression were less in the methylprednisolone group than in the control group but did not reach statistical significance. These results indicate that methylprednisolone significantly reduces the production of IL-8 in an isolated CPB system. This effect occurs in the absence of IL-10.

Methylprednisolone favourably alters plasma and urinary cytokine homeostasis and subclinical renal injury at cardiac surgery.

UNLABELLED: Whilst elevated urinary transforming growth factor beta-1 (TGFbeta) is associated with chronic renal dysfunction its role in acute peri-operative renal dysfunction is unknown. In contrast, peri-operative increases in urinary IL-1 receptor antagonist (IL-1ra) and TNF soluble receptor-2 (TNFsr-2) mirror pro-inflammatory activity in the nephron and correlate with renal complications. Steroids modulate some plasma cytokines (decreasing TNFalpha, IL-8, IL-6 and increasing IL-10), whereas ability to reduce plasma and urinary TNFsr-2 and IL-1ra and peri-operative renal injury is unknown. Patients undergoing coronary artery bypass grafting with cardiopulmonary bypass (CPB) were randomised to receive methylprednisolone (n = 18) or placebo (n = 17) before induction of anaesthesia. Plasma and urinary pro- and anti-inflammatory cytokine balance was determined along with subclinical proximal tubular injury and dysfunction, measured by urinary N-acetyl-beta-d-glucosaminidase (NAG)/creatinine and alpha-1-microglobulin/creatinine ratios, respectively. In the control group compared with baseline, plasma IL-8, TNFalpha, IL-10, IL-1ra and TNFsr-2 were significantly elevated along with urinary IL-1ra, TNFsr-2 and TGFbeta1. Urinary NAG/creatinine and alpha-1-microglobulin/creatinine ratios rose from completion of revascularisation until 6 h with recovery at 24 h with a further rise in NAG/creatinine ratio at 48 h. Compared to placebo, the methylprednisolone group showed significantly reduced plasma IL-8, TNFalpha, IL-1ra and TNFsr-2 whereas plasma IL-10 increased. Compared to placebo, the methylprednisolone group demonstrated significantly reduced urinary NAG/creatinine ratio, TNFsr-2 and TGFbeta1 at 24 h whereas urinary alpha-1-microglobulin/creatinine ratios increased. CONCLUSIONS: Methylprednisolone administration during cardiac surgery significantly reduces plasma and urinary TNFsr-2 and IL-1ra, urinary TGFbeta1 and subclinical renal injury but not dysfunction.

The chemoattractants, IL-8 and formyl-methionyl-leucyl-phenylalanine, regulate granulocyte colony-stimulating factor signaling by inducing suppressor of cytokine signaling-1 expression.

Suppressors of cytokine signaling (SOCS) are encoded by immediate early genes known to inhibit cytokine responses in a classical feedback loop. SOCS gene expression has been shown to be induced by many cytokines, growth factors, and innate immune stimuli, such as LPS. In this paper, we report that the chemoattractants, IL-8 and fMLP, up-regulate SOCS1 mRNA in human myeloid cells, primary human neutrophils, PBMCs, and dendritic cells. fMLP rapidly up-regulates SOCS1, whereas the induction of SOCS1 upon IL-8 treatment is delayed. IL-8 and fMLP did not signal via Jak/STATs in primary human macrophages, thus implicating the induction of SOCS by other intracellular pathways. As chemoattractant-induced SOCS1 expression in neutrophils may play an important role in regulating the subsequent response to growth promoting cytokines like G-CSF, we investigated the effect of chemoattractant-induced SOCS1 on cytokine signal transduction. We show that pretreatment of primary human neutrophils with fMLP or IL-8 blocks G-CSF-mediated STAT3 activation. This study provides evidence for cross-talk between chemoattractant and cytokine signal transduction pathways involving SOCS proteins, suggesting that these chemotactic factors may desensitize neutrophils to G-CSF via rapid induction of SOCS1 expression.