Anti-CSF3 monoclonal antibody, clone FQS4314(O)(C)

RAW264.7 mouse macrophages were incubated with immunostimulatory CpG ODN and/or poly (I:C), and changes in global mRNA expression levels monitored at 4 and 12 hr using a 36 K mouse microarray. Genes encoding the cytokines IL6, IL1A, IFNA6, IFNB1, and CSF3 were synergistically up-regulated at 4 hours while those encoding IL33, IL6, IL12A, IL12B, IL19, IL10, and IL1F6 were synergistically activated at 12 hours. The interleukins IL33, IL19, IL12A, the chemokine S100A8 and the neurotransmitter NPY genes were not activated individually by either CpG ODN or poly(I:C) but were strongly up-regulated following combined stimulation. These data represent the first evidence of synergistic transcriptional activation of the interleukin genes IL33 and IL19, and help to explain the mechanism by which CpG ODN and poly(I:C) combine to enhance immune responses in vitro and in vivo.

Polyamines have been implicated in numerous biological processes, including inflammation and carcinogenesis. Homeostatic regulation leads to interconversion of the polyamines putrescine and the downstream metabolites spermidine and spermine. The enzyme spermine oxidase (SMOX), which back-converts spermine to spermidine, contributes to regulation of polyamine levels, but can also have other effects. We have implicated SMOX in gastric inflammation and carcinogenesis due to infection by the pathogen Helicobacter pylori. In addition, we reported that SMOX can be upregulated in humans with inflammatory bowel disease. Herein, we utilized Smox-deficient mice to examine the role of SMOX in two murine colitis models, Citrobacter rodentium infection and dextran sulfate sodium (DSS)-induced epithelial injury. In C. rodentium-infected wild-type (WT) mice, there were marked increases in colon weight/length and histologic injury, with mucosal hyperplasia and inflammatory cell infiltration; these changes were ameliorated in Smox(-/-) mice. In contrast, with DSS, Smox(-/-) mice exhibited substantial mortality, and increased body weight loss, colon weight/length, and histologic damage. In C. rodentium-infected WT mice, there were increased colonic levels of the chemokines CCL2, CCL3, CCL4, CXCL1, CXCL2, and CXCL10, and the cytokines IL-6, TNF-alpha, CSF3, IFN-gamma, and IL-17; each were downregulated in Smox(-/-) mice. In DSS colitis, increased levels of IL-6, CSF3, and IL-17 were further increased in Smox(-/-) mice. In both models, putrescine and spermidine were increased in WT mice; in Smox(-/-) mice, the main effect was decreased spermidine and spermidine/spermine ratio. With C. rodentium, polyamine levels correlated with histologic injury, while with DSS, spermidine was inversely correlated with injury. Our studies indicate that SMOX has immunomodulatory effects in experimental colitis via polyamine flux. Thus, SMOX contributes to the immunopathogenesis of C. rodentium infection, but is protective in DSS colitis, indicating the divergent effects of spermidine.