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Anti-inflammatory response of IL-4, IL-10 and TGF-beta in patients with systemic inflammatory response syndrome.

The systemic inflammatory response syndrome (SIRS) is an inflammatory process seen in association with a large number of clinical infective and non-infective conditions. The aim of this study was to investigate the role of anti-inflammatory cytokines such as interleukin-4 (IL-4), interleukin-10 (IL-10), and transforming growth factor-beta (TGF-beta). Serum levels of IL-4, IL-10 and TGF-beta were determined in 45 patients with SIRS: 38 patients had SIRS of infectious origin, whereas seven patients had non-infectious SIRS. Twenty healthy subjects were used as controls. Serum levels of IL-4, IL-10 and TGF-beta were determined by an immunoenzyme assay. A significant increase of IL-4 was observed in these patients at the time of diagnosis and 5 days later. In contrast, serum levels of IL-10 were not increased at the time of diagnosis, but a slight decrease was noted after 5 days. Serum levels of TGF-beta were not increased at time of diagnosis, and a slight increase was observed after 5 days. Serum levels of IL-4 were significantly higher in patients with infectious SIRS at the time of diagnosis, whereas no significant difference between infectious and non-infectious SIRS was noted for serum levels of IL-10 and TGF-beta at the time of diagnosis and 5 days later. During SIRS, serum levels of IL-4 were significantly increased with a significant correlation between IL-4 and mortality, and only levels of IL-4 were significantly increased in the SIRS caused by infectious stimuli.


Introduction
The systemic inflammatory response syndrome (SIRS) is an inflammatory process seen in association with a number of clinical infective and non-infective conditions. 1 Besides the infectious insults caused by viruses, protozoa and bacteria that may cause SIRS, non-infectious causes may include pancreatitis, multiple trauma, ischaemia, haemorrhagic shock and immune-mediated organ injury. 1 In response to an infectious or non-infectious stimulus, the local environment produces cytokines which are primarily intended to evoke an inflammatory response, and successively small quantities of inflammatory cytokines are released into the circulation to enhance local response. 2 Several agents have been studied for their role as mediators of sepsis and septic shock, including bacterial toxins, cytokines and nitric oxide. 3 -5 Acute-phase response is initiated by tumour necrosis factor (TNF), Il-1, and the IL-8 family, which are grouped together and called proinflammatory cytokines. 6 Successively, acute-phase response is con-trolled by a simultaneous decrease in proinflammatory mediators and release of endogenous antagonists. It is well known that IL-4, IL-10 and transforming growth factor b (TGF-b) are considered anti-inflammatory cytokines because, when administered to animals with infection or inflammation, they reduce the severity of disease and reduce the production of IL-1 and TNF. 7 In this study we determined serum levels of antiinflammatory cytokines IL-4, IL-10 and TGF-b in patients with infectious and non-infectious SIRS, to evaluate whether an anti-inflammatory cytokine profile is associated with an adverse outcome. Blood samples were collected at the time of diagnosis of SIRS, and 5 days later. Serum was prepared by centrifugation at 1600 ´g for 10 min, and stored at -75°C. The concentration of IL-4, IL-10 and TGF-b was measured by using the ELISA technique (R and D Systems, Minneapolis, MN, USA). The sensitivity of ELISA kits to IL-4 and and IL-10 was equal to or less than 5 pg/mL in all cases, whereas the sensitivity to TGF-b was equal to or less than 7 pg/mL. Data are expressed as mean and standard deviation, and were compared using the non-parametric Mann-Whitney U test. Statistical analysis was performed with the significance level set at p < 0.05.

Results
Serum levels of IL-4, IL-10 and TGF-b were determined in patients with infectious or non-infectious SIRS. In addition, serum levels of IL-4, IL-10 and TGFb were determined in 25 healthy control subjects (IL-4: 3.2 ± 1.2 pg/mL; IL-10: 1.1 ± 2.3 pg/mL; TGF-b: 4.1 ± 1.9 pg/mL). Serum levels of IL-4, IL-10 and TGF-b were determined in patients with infectious and noninfectious SIRS at the time of diagnosis and 5 days later. A significant increase in serum levels of IL-4 was observed in patients with SIRS at the time of diagnosis, whereas Il-4 levels did not significantly change 5 days later (Table 1). Furthermore, serum levels of IL-4 were significantly higher in patients with infectious SIRS than in those with non-infectious SIRS at the time of diagnosis (   1, set B). In addition, serum levels of TGF-b were not significantly different between patients with infectious SIRS and non-infectious SIRS either at the time of diagnosis or 5 days later (Table 1, set A and B). Table 2 shows serum levels of IL-4, IL-10 and TGFb in survivor and non-survivor patients with SIRS at the time of diagnosis and 5 days later, respectively. As can be seen in Table 2, we did not find a significant correlation between serum levels of IL-4, IL-10 and TGF-b and risk of death in patients with SIRS at the time of diagnosis. In contrast, IL-4 was significantly associated with a fatal outcome in patients with SIRS.

Discussion
The results of this study show that response of antiinflammatory cytokines Il-10 and TGF-b was not significantly increased in early and late stages of SIRS, whereas high circulating levels of IL-4 were found in early and late stages of SIRS, with a significant correlation between IL-4 and mortality. In addition, only levels of IL-4 were significantly increased in SIRS caused by infectious stimuli. The pro-inflammatory state of the acute phase response to infectious or noninfectious stimuli also initiates anti-inflammatory activity involving mediators such as IL-4, IL-10, IL-11, TGF-b and IL-ra. 8 Eventually, they should stimulate a compensatory systemic anti-inflammatory response to downregulate the pro-inflammatory response. 9 In particular, IL-4 is able to downregulate human alveolar macrophages and peripheral blood monocytes, stimulated by bacterial endotoxin, to produce IL-1a and IL-1b and TNF-a. 10 More recently, van Dissel e t a l. 11 have shown that febrile patients with early and advanced stages of SIRS had a fatal outcome with a high ratio of IL-10 to TNF-a. These findings shed new light on the debate concerning the efficacy and safety of pro-inflammatory cytokine inhibition in the management of sepsis.
By blocking the action of pro-inflammatory cytokines, the circulating cytokine profile may be forced into anti-inflammatory cytokine activation that results in exacerbation of systemic disease and adverse outcome in febrile patients. The mechanisms that determine the amount and balance of various proinflammatory and anti-inflammatory cytokines are still largely unknown. The pro-and anti-inflammatory mechanisms are often dysregulated by several host and microbial factors, which determine the pattern and magnitude of the human cytokine response involved in infection.
In conclusion, compensatory systemic anti-inflammatory response which downregulates the proinflammatory response has not been fully clarified yet, and the possible therapeutic activity of antiinflammatory cytokines is not supported by current experimental and clinical studies.