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Generation of Diversity in the Innate Immune System: Macrophage Heterogeneity Arises from Gene-Autonomous Transcriptional Probability of Individual Inducible Genes¹

Timothy Ravasi^*,, Christine Wells^*,, Alistair Forest^*, David M. Underhill, Brandon J. Wainwright^*, Alan Aderem, Sean Grimmond^* and David A. Hume^2,*,

^* Institute for Molecular Bioscience, and Cooperative Research Center for Chronic Inflammatory Diseases, University of Queensland, Brisbane, Queensland, Australia; and Institute for Systems Biology, Seattle, WA 98105

Microbial products such as LPS stimulate macrophages to produce a wide diversity of inducible gene products needed for immediate host defense and priming of an appropriate acquired immune response. In this study, we have examined LPS-inducible gene expression in subclones of a mouse macrophage cell line, RAW264, using cDNA microarrays. Even archetypal target genes such as TNF- were not induced in all subclones, and there was no absolute correlation between expression of pairs of genes. Nevertheless, the array analysis revealed clusters of genes that were more likely to be coexpressed. RAW264 cells stably transfected with luciferase reporter genes driven by LPS-responsive promoters revealed the same kind of clonal heterogeneity. The results indicate that each LPS-inducible gene has its own inherent probability of activation in response to LPS.

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