title: The immune-body cytokine network defines a social architecture of cell interactions.
abstract: BACKGROUND
  Three networks of intercellular communication can be associated with cytokine secretion; one limited to cells of the immune system (immune cells), one limited to parenchymal cells of organs and tissues (body cells), and one involving interactions between immune and body cells (immune-body interface). These cytokine connections determine the inflammatory response to injury and subsequent healing as well as the biologic consequences of the adaptive immune response to antigens. We informatically probed the cytokine database to uncover the underlying network architecture of the three networks.
  
  
  RESULTS
  We now report that the three cytokine networks are among the densest of complex networks yet studied, and each features a characteristic profile of specific three-cell motifs. Some legitimate cytokine connections are shunned (anti-motifs). Certain immune cells can be paired by their input-output positions in a cytokine architecture tree of five tiers: macrophages (MPhi) and B cells (BC) comprise the first tier; the second tier is formed by T helper 1 (Th1) and T helper 2 (Th2) cells; the third tier includes dendritic cells (DC), mast cells (MAST), Natural Killer T cells (NK-T) and others; the fourth tier is formed by neutrophils (NEUT) and Natural Killer cells (NK); and the Cytotoxic T cell (CTL) stand alone as a fifth tier. The three-cell cytokine motif architecture of immune system cells places the immune system in a super-family that includes social networks and the World Wide Web. Body cells are less clearly stratified, although cells involved in wound healing and angiogenesis are most highly interconnected with immune cells.
  
  
  CONCLUSIONS
  Cytokine network architecture creates an innate cell-communication platform that organizes the biologic outcome of antigen recognition and inflammation. Informatics sheds new light on immune-body systems organization.
  
  
  METHODS
  This article was reviewed by Neil Greenspan, Matthias von Herrath and Anne Cooke.
authors.affiliation: Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel. ziv.frankenstein@weizmann.ac.il
authors.forename: Ziv
authors.initials: Z
authors.lastname: Frankenstein
authors.forename: Uri
authors.initials: U
authors.lastname: Alon
authors.forename: Irun R
authors.initials: IR
authors.lastname: Cohen