ABSTRACT
BACKGROUND/PURPOSE: Cytokines are essential for the prevention of microbial infections. Total parenteral nutrition (TPN) in infancy is associated with an increased risk of infection, and this could be related to altered cytokine production. The aim of the study was to determine if cytokine production is altered in monocytes from surgical infants receiving TPN. METHODS: There were 3 study groups: (a) infants receiving TPN, (b) enterally fed healthy control infants, and (c) enterally fed healthy control adults. Blood samples were incubated with either Escherichia coli LPS, Staphylococcus epidermidis, or with medium alone. Flow cytometry was used to measure monocyte intracellular cytokine: tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-1beta. RESULTS: After LPS stimulation, the percent of monocytes producing TNF-alpha and IL-6 were lower in infants on TPN than both control infants and adults. This was most apparent for TNF-alpha. The difference for IL-1beta was significant only between infant on TPN and control adults. When blood was stimulated with S. epidermidis, all 3 cytokines were significantly lower in the TPN group compared with control adults. However, the differences between infants on TPN and infant controls only reached statistical significance for IL-6. CONCLUSIONS: The inflammatory response to bacterial challenge is impaired in infants on TPN compared with enterally fed infants or adults. The pattern of this response may be dependent on the nature of the microbial challenge. Our results indicate that the susceptibility of TPN-fed surgical infants to bacterial infections may in part be caused by impaired cytokine responses after bacterial invasion.
Subject(s)
Cytokines/biosynthesis , Monocytes/immunology , Monocytes/metabolism , Parenteral Nutrition, Total/adverse effects , Surgical Procedures, Operative , Adult , Escherichia coli/immunology , Humans , Infant , Interleukin-1/biosynthesis , Interleukin-6/biosynthesis , Lipopolysaccharides/pharmacology , Parenteral Nutrition, Total/methods , Staphylococcus epidermidis/immunology , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
Tumour necrosis factor-alpha (TNF-alpha), IL-1alpha and IL-6 production by human monocytes in response to a clinical strain of the Gram-negative encapsulated bacteria Neisseria meningitidis and an isogenic lpxA- strain deficient in LPS was investigated. Wild-type N. meningitidis at concentrations between 105 and 108 organisms/ml and purified LPS induced proinflammatory cytokine production. High levels of these cytokines were also produced in response to the lpxA- strain at 107 and 108 organisms/ml. The specific LPS antagonist bactericidal/permeability-increasing protein (rBPI21) inhibited cytokine production induced by LPS and wild-type bacteria at 105 organisms/ml but not at higher concentrations, and not by LPS-deficient bacteria at any concentration. These data show that proinflammatory cytokine production by monocytes in response to N. meningitidis does not require the presence of LPS. Therapeutic strategies designed to block LPS alone may not therefore be sufficient for interrupting the inflammatory response in severe meningococcal disease.
Subject(s)
Interleukin-1/biosynthesis , Interleukin-6/biosynthesis , Lipopolysaccharides/immunology , Monocytes/immunology , Neisseria meningitidis/immunology , Tumor Necrosis Factor-alpha/biosynthesis , Acyltransferases/genetics , Acyltransferases/physiology , Cells, Cultured , Gene Deletion , Humans , Lipopolysaccharides/antagonists & inhibitors , Membrane Proteins/pharmacology , Monocytes/cytology , Monocytes/drug effects , Monocytes/microbiology , Neisseria meningitidis/geneticsABSTRACT
The aim of this study was to investigate the effect of absent CD40-CD40 ligand interactions in patients with X-linked hyper-IgM syndrome (XHIGM) on the generation of Th1 and Th2 immunity. Whole blood from patients and sex- and age-matched controls was stimulated with phorbol myristate acetate (PMA) and calcium ionophore A23187 in the presence of Brefeldin A. After 5 h, cellular production of interferon-gamma, IL-4, tumour necrosis factor-alpha and IL-2 was measured by intracellular cytokine staining and flow cytometry. This method has been shown previously to preferentially activate memory T cells and in preliminary experiments cells making these cytokines were found to be predominantly CD45RO+. No differences in the proportion of T cells (CD3+) or T cell subsets (CD4+/CD8+) secreting these cytokines between XHIGM patients and age- and sex-matched controls were observed. In addition, production of IL-12 and IL-6 by monocytes in response to lipopolysaccharide and CD40 stimulation was equivalent in patients and controls. These results suggest that development of Th1 or Th2 memory cells in patients with XHIGM is unaffected by the absence of functional CD40 ligand. Rather, the susceptibility of these patients to intracellular pathogens, such as Pneumocystis carinii and Cryptosporidium parvum, is more likely to be due to an inability to activate the effector arm of the cellular immune response.