Gpnmb is induced in macrophages by IFN-gamma and lipopolysaccharide and acts as a feedback regulator of proinflammatory responses

Vera M Ripoll, Katharine M Irvine, Timothy Ravasi, Matthew J Sweet, David A Hume

Research output: Contribution to journalArticlepeer-review

Abstract

The process of inflammation requires the selective expression of a suite of genes in cells of the macrophage lineage. To identify candidate regulators of inflammation, we used cDNA microarrays to compare the transcriptome of inflammatory macrophages (thioglycolate-elicited peritoneal macrophages), bone marrow-derived macrophages, nonadherent spleen cells, and fibroblasts. We identified genes that were macrophage restricted and further elevated in inflammatory macrophages, and characterized the function of one such gene, gpnmb. Gpnmb mRNA expression was enriched in myelomonocytic cell lines and macrophage-related tissues and strongly up-regulated during macrophage differentiation. Epitope-tagged GPNMB expressed in RAW264.7 cells exhibited a perinuclear distribution and colocalized with the Golgi marker coat protein beta. Upon activation of macrophages with IFN-gamma and LPS, GPNMB translocated from the Golgi apparatus to vesicular compartments scattered toward the periphery. Gpnmb overexpression in RAW264.7 cells caused a 2-fold reduction in the production of the cytokines IL-6 and IL-12p40 and the inflammatory mediator NO in response to LPS. DBA mice, which have an inactivating point mutation in the gpnmb gene, exhibited reduced numbers of myeloid cells, elevated numbers of thioglycolate-elicited peritoneal macrophages, and higher levels of proinflammatory cytokines in response to LPS. Thus, GPNMB acts as a negative regulator of macrophage inflammatory responses.
Original languageEnglish
Pages (from-to)6557-66
Number of pages10
JournalJournal of Immunology
Volume178
Issue number10
Publication statusPublished - 15 May 2007

Keywords

  • Animals
  • Bone Marrow Cells
  • Cell Differentiation
  • Cell Line
  • Cell Line, Tumor
  • Conserved Sequence
  • Eye Proteins
  • Feedback, Physiological
  • Humans
  • Inflammation Mediators
  • Interferon-gamma
  • Lipopolysaccharides
  • Macrophage Activation
  • Macrophages
  • Membrane Glycoproteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Mutant Strains
  • RNA, Messenger
  • Repressor Proteins

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