Modulation Of Cytokine Levels Research Articles

Ceftiofur Regulates LPS-Induced Production of Cytokines and Improves LPS-Induced Survival Rate in Mice

The influence of ceftiofur on immune responses has been suggested by results of in vitro studies. This effect was studied using a murine model that measured mortality and early cytokine responses after challenge with endotoxin. To investigate the treatment of endotoxic mice with ceftiofur, mice were pretreated with ceftiofur at different times before and after challenge with a lethal dose of 30 mg/kg lipopolysaccharide (LPS). We found that 20 mg/kg ceftiofur had a significant protective effect and reduced the mortality of mice at early stages. To further understand the mechanism of action of ceftiofur, we examined plasma cytokine levels. Mice treated with LPS alone showed markedly increased plasma levels of TNF-alpha, IL-1beta, IL-6 and IL-10, whereas mice pretreated with 20 mg/kg ceftiofur showed significantly decreased plasma levels of TNF-alpha, IL-1beta and IL-6, but increased plasma levels of IL-10. These results support the idea that ceftiofur has a beneficial effect on LPS-induced endotoxemia caused by LPS through its modulation of cytokine levels. This confirms the effect of ceftiofur for the treatment of endotoxemia, which is caused by a Gram-negative bacterial infection.

Inflammatory Breast Diseases during Lactation: Health Effects on the Newborn—A Literature Review

Breastfeeding-associated inflammatory breast diseases appear especially during the first twelve weeks postpartum and are the most common reason for early cessation of breastfeeding. It also becomes increasingly evident that these inflammatory mammary diseases are triggered or perpetuated in a large part by psychosocial stress. Immunological processes taking place during this cascade in the mammary gland and consequences for the breastfeed newborn are mostly yet unknown. This review summarizes insights from studies on modulation of cytokine levels in breast milk during inflammatory processes like milk stasis and mastitis systematically. It also gives an overview on possible pathological effects, which these cytokine changes in the breast milk might have on the newborn.

CAPSULE AND O-ANTIGEN FROM AN EXTRAINTESTINAL ISOLATE OF ESHERICHIA COLI MODULATE CYTOKINE LEVELS IN RAT MACROPHAGES IN VITRO AND IN A RAT MODEL OF PNEUMONIA

Gram-negative pneumonia results in significant morbidity, mortality, and cost to the healthcare system. Previously the authors demonstrated that capsule and O-antigen, virulence factors of the extraintestinal Escherichia coli isolate CP9, modulate pulmonary neutrophil influx in a rat pneumonia model. In this report, the authors utilized CP9 and mutants deficient in O-antigen (CP921), capsule (CP9.137), or both (CP923) to test the hypothesis that modulation of cytokine levels by capsule and/or O-antigen may be a contributory mechanism. Effects of capsule and O-antigen on cytokine levels in rats in vivo and in isolated pulmonary macrophages in vitro were assessed. In vivo, capsule and O-antigen had no significant effect on tumor necrosis factor (TNF)-α levels in bronchoalveolar lavage fluid (BALF), but both were associated with significant increases in the levels of interleukin (IL)-1β and Cytokine-induced neutrophil Chemoattractant-1 (CINC-1). However, potential difficulties in interpreting data occurred because challenge bacterial strains exhibited differential growth, and clearance characteristics and mixed cell populations were present. Therefore, added mechanistic studies investigated specific interactions of capsule and O-antigen with pulmonary macrophages purified from normal rats and exposed to CP9, CP921, CP9.137, or CP923 in vitro. Results indicated that the presence of capsule led to significantly increased levels of TNF-α, IL-1β, and CINC-1, whereas O-antigen significantly decreased macrophage-associated levels of these mediators. These findings support the hypothesis that CP9 capsule is proinflammatory for macrophage-induced neutrophil recruitment, whereas O-antigen attenuates macrophage production of proinflammatory mediators in pneumonia. These results expand our understanding on the mechanisms by which these virulence traits may contribute to the inflammatory pathogenesis of pneumonia.

IL-21 modulates cytokine levels in murine collagen-induced arthritis and contributes to disease pathology

IL-21 modulates cytokine levels in murine collagen-induced arthritis and contributes to disease pathology

Proinflammatory and Th1 cytokine alterations following ultraviolet radiation enhancement of disease due to influenza infection in mice.

Exposure of rodents to immunosuppressive agents such as ozone, dioxin, or ultraviolet radiation (UVR) leads to increased morbidity and mortality following influenza virus infection. However, these adverse effects are not related to the suppression of virus-specific immune responses. Our laboratory showed that UVR increased the morbidity, mortality, and pathogenesis of influenza virus without affecting protective immunity to the virus, as measured by resistance to reinfection, suggesting that UVR and other immunosuppressive pollutants such as dioxin and ozone may exacerbate early responses that contribute to the pathogenesis of a primary viral infection. In the present study, we examined the mechanism of UVR-enhanced mortality in the absence of effects on virus-specific immunity and tested the hypothesis that modulation of cytokine levels was associated with increased deaths and body weight loss. BALB/c mice were exposed to 8.2 kJ/m(2) UVR and were infected 3 days later with a sublethal influenza virus infection (LD(40) of mouse-adapted Hong Kong influenza A/68, H(3)N(2)). Influx of inflammatory cells, proinflammatory cytokines, and cytokines produced by T-helper lymphocytes (Th1 and Th2) were measured in lung homogenates (LH) as well as in bronchoalveolar lavage fluid (BAL). UVR preexposure decreased the influenza-induced lymphocytic influx 5 days after infection, but did not alter macrophage and neutrophil influx into the lung, or increase virus titers significantly. Although interferon (IFN)-gamma, total interleukin (IL)-12, IL-6, and TNF-alpha were altered in mice that received UVR exposure prior to infection, no clear association was made that correlated with the UVR-induced increase in body weight loss and mortality due to influenza infection.

Cytokine regulation of gingival fibroblast lysyl oxidase, collagen, and elastin.

Systemic therapy with cyclosporin A, phenytoin, and nifedipine modulates cytokine levels in human gingival tissues. Functional relationships between altered cytokine levels and gingival extracellular matrix production are partially characterized. The present study investigates in cultured human gingival fibroblasts the regulation of lysyl oxidase, alpha-1 type I collagen, and elastin by selected cytokines that are elevated in drug-induced gingival overgrowth tissues. Normal human gingival fibroblasts were cultured and then treated with selected cytokines: interleukin (IL)-1beta, IL-6, platelet-derived growth factor (PDGF)-BB, and basic fibroblast growth factor (bFGF or FGF-2). Cells were harvested at intervals, and changes in lysyl oxidase enzyme activity, and in mRNA levels of lysyl oxidase, alpha-1 type I collagen, and elastin were determined. bFGF reproducibly and significantly decreased human gingival fibroblast lysyl oxidase and alpha-1 type I collagen mRNA levels in a dose- and time-dependent manner; 1 nM bFGF reduced lysyl oxidase and collagen mRNA levels to 53% and to less than 10% of control after 48 hours of treatment. Interestingly, bFGF downregulated lysyl oxidase enzyme activity by 10% to 20%. IL-1, IL-6, and PDGF-BB did not significantly regulate lysyl oxidase enzyme activity, or alpha-1 type I collagen, elastin, and lysyl oxidase mRNA levels under the conditions tested. Previous studies have shown that modulated levels of bFGF occur in gingiva as a result of certain pharmacologic therapies. The present study suggests that modulated levels of bFGF likely influence gingival connective tissue metabolism.

Effect of trypsin–chymotrypsin (Chymoral Forte D.S.) preparation on the modulation of cytokine levels in burn patients

The present study was carried out in burn patients administered with Trypsin–Chymotrypsin (Chymoral Forte D.S.) preparation to observe if the acute-phase protein levels in the serum are modulated through the synthesis of IL-1β and IL-6 and if the severity of the inflammatory phase could be regulated. The effects of Trypsin–Chymotrypsin preparation on the modulation of cytokine levels particularly, IL-6 and IL-1β were analyzed in serum samples of 15 burn patients and compared with untreated controls. Significant differences in cytokine levels ( P<0.05) were observed in untreated burn patients and Trypsin–Chymotrypsin preparation treated patients. There were significant variations in serum IL-6 and IL-1β on the day of admission and post burn day 10 in treated as well as untreated burn patients. Patients with a higher percentage of total body surface area and sepsis showed a significant increase in IL-1β and IL-6 in the serum. An increase in serum levels of both cytokines was observed on post burn day 1 and a significant decrease was observed in Trypsin–Chymotrypsin preparation treated patients on days 7 and 10. The possible role of the inflammatory cytokines in the pathophysiology of burns is discussed.

Unintended immunomodulation: part II. Effects of pharmacological agents on cytokine activity.

Cytokines are proteins that are produced by immune and non-immune cells, and they function as mediators to facilitate cellular communication. Their production is regulated by a complex network of co-stimulatory and feedback loops that responds to a variety of stimuli. Several pharmacological agents have been found to alter systemic concentrations and/or the activity of different cytokines via a variety of mechanisms, including changes in biosynthesis, secretion, and/or stability. Many of the agents that modulate cytokine levels commonly are used in the management of critically ill patients. Catecholamines for example, have been found to promote the secretion of anti-inflammatory cytokines, and, therefore, may alter acute inflammatory processes such as sepsis. Antimicrobials have multiple effects on cytokine production, either secondary to the release of endotoxins from gram-negative bacteria or via direct activity on cytokine expression at the transcriptional and/or post-transcriptional level. Pentoxifylline has multiple effects on the immune system, but inhibition of pro-inflammatory cytokine release predominates. The reminder of the known drug-cytokine interactions and their effect on the inflammatory process are discussed. Information on the pharmacodynamic effect of drugs is limited, and our understanding of the clinical significance of these observations awaits further investigation. This review was designed to provide intensivists and other clinicians with useful information regarding the effect of medications on cytokine activity. It is also intended to help researchers and clinicians to optimize the design of studies of pharmacotherapeutic modulation of cytokines and to avoid the use of some agents in clinical circumstances in which cytokine manipulation is undesirable.

Attenuation of catecholamine-induced immunosuppression in whole blood from patients with sepsis.

Studies performed on healthy volunteers have revealed that catecholamines down-regulate the lipopolysaccharide (LPS)-induced production of tumor necrosis factor (TNF)alpha, interleukin (IL)-6, and IL-1beta. We extended this observation and show that this effect is based on changes in the mRNA concentration of these cytokines. Catecholamines are increased in severe sepsis due to endogenous production and have to be administered exogenously when the disease has proceeded to the state of prolonged hypotension. We here investigated whether the immunomodulating effect of catecholamines could also be demonstrated in the blood of patients with prolonged severe sepsis and of those in prolonged septic shock. Blood was stimulated ex vivo with LPS in the presence and absence of epinephrine and the cytokine protein concentration was determined. In blood of healthy volunteers, epinephrine reduced the LPS-stimulated synthesis of TNFalpha by 62.5% (P< 0.0001), of IL-6 by 39% (P< 0.0001), and of IL-1beta by 40% (P= 0.015), and increased the LPS-stimulated IL-10 production by 77.8% (P < 0.0001). Correspondingly, in blood of patients with prolonged severe sepsis, TNFalpha was reduced by 67.2% (P < 0.0001) and IL-6 was reduced by 32.9% (P < 0.0001); IL-1beta and IL-10 were not modulated by catecholamines in these patients. In blood samples of patients in prolonged septic shock, epinephrine did not modulate cytokine levels of IL-6 and IL-10, and decreased TNFalpha only by 36.4% (P < 0.0001). Interestingly, epinephrine suppressed the IL-1beta production by 73% (P < 0.0001) in blood of patients in prolonged septic shock, which was twice as much as in blood samples of healthy volunteers. The altered response of septic blood to catecholamines might be due to an altered reactivity of leukocytes in the prolonged disease although an additional role of preexisting catecholamines cannot be completely excluded.

Section Reviews: Pulmonary-Allergy, Dermatological, Gastrointestinal &amp; Arthnlis: New therapeutic approaches to atopic dermatitis

Atopic dermatitis (AD) is a chronic inflammatory skin disease which affects some 10 - 15% of the population during childhood. The prevalence of the disease is increasing and there are few, if any, current therapies which are directed at the underlying cause of the disease. A better understanding of the mechanisms of AD is starting to offer potential therapeutic approaches to this disease. The understanding of the role of cytokines in AD, in particular interleukin-4, interferon-gamma and tumour necrosis factor-alpha, has indicated several potential approaches, including inhibition of cytokine processing (matrix metalloproteinase inhibitors), inhibition of cytokine release (phosphodiesterase type IV inhibitors) and modulation of cytokine levels, as well as newer approaches to immunomodulation.