Cellular and Molecular Mechanisms of the Selective Regulation of Il-12 Production by 12/15-lipoxygenase.
From: The Wistar Institute, Philadelphia, PA 19104, USA.
Journal of immunology (Baltimore, Md. : 1950)
- Publish Date: Jan 2006
- ISSN: 0022-1767
- Volume: 176
- Issue: 1
- Pages: 265-74
- Medium: Print
- Language: English
- Citation (JAMA): Middleton Melissa K, Rubinstein Tanya, Puré Ellen, et al. Cellular and Molecular Mechanisms of the Selective Regulation of Il-12 Production by 12/15-lipoxygenase.. J. Immunol. Jan 2006;176:265-74
Abstract
IL-12 drives type I immune responses and can mediate chronic inflammation that leads to host defense as well as disease. Recently, we discovered a novel role for 12/15-lipoxygenase (12/15-LO) in mediating IL-12p40 expression in atherosclerotic plaque and in isolated macrophages. We now demonstrate that 12/15-LO regulates IL-12 family cytokine production in a cell-type and stimulus-restricted fashion. LPS-stimulated elicited peritoneal macrophages derived from 12/15-LO-deficient (Alox15) mice produced reduced IL-12 and IL-23 levels, but comparable amounts of several other inflammatory mediators tested. Furthermore, LPS stimulation triggered an increase in wild-type macrophage 12/15-LO activity, whereas pharmacological inhibition of 12/15-LO activity suppressed LPS-induced IL-12 production in wild-type macrophages. 12/15-LO-deficient macrophages also produced reduced levels of IL-12 in response to TLR2 stimulation, but not in response to CpG (TLR9) or CD40/CD40L-mediated activation. In contrast to our previous finding of reduced IL-12 production in the setting of atherosclerosis, we found that comparable IL-12 levels were produced in Alox15 and wild-type mice during an acute response to LPS in vivo. This paradox may be explained by normal production of IL-12 by 12/15-LO-deficient neutrophils and dendritic cells, which are major sources of IL-12 during acute inflammation. Finally, we detected selectively decreased association of the transcription factors IFN consensus sequence binding protein and NF-kappaB with the IL-12p40 promoter in 12/15-LO-deficient macrophages. Taken together, these findings reveal a highly selective pathway to IL-12 production that may prove a useful target in chronic inflammation while sparing the acute response to infection.
Mesh Headings (Keywords): Animals, Arachidonate 12-Lipoxygenase, Arachidonate 15-Lipoxygenase, Cells, Cultured, Cytokines, Enzyme-Linked Immunosorbent Assay, Female, Humans, Interferon Regulatory Factors, Interferon Type II, Interleukin-12, Macrophage Activation, Macrophages, Peritoneal, Male, Mice, NF-kappa B, Protein Subunits, Reverse Transcriptase Polymerase Chain Reaction
Check for Full Text / PubMed Unique Identifier (PMID): 16365418
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