IL-15 constrains mast cell-dependent antibacterial defenses by suppressing chymase activities

Nature Medicine 13: 927-934 (2007)

Speaker：黃千晏                                           Time：14:10~15:00, September 19, 2007

Commentator：王崇任 醫師                         Place：Room 601

Abstract：

Sepsis is a serious clinical problem with systemic inflammation caused by infection, and 60% of the causal pathogens are gram-negative (GN) bacteria. Previous studies have shown that the mast cells (MCs) can modulate the host’s innate immune responses to GN bacteria via phagocytosingbacteria, presenting bacterial antigens to T cells and recruiting phagocytes through the release of pro-inflammatory mediators, such as proteases (1). MC proteases activate the chemokines through enzymatic cleavage. IL-15 is a ‘first line of defense’ cytokine secreted by many cells including MCs (2, 3). The authors hypothesized that IL-15 may play a role in MC-dependent antibacterial defense during sepsis by regulating the MC protease activity. They demonstrated that the recruitment of neutrophils and bacterial clearance as well as the survival rate of mice with acute septic peritonitis elaborated by cecal ligation and puncture (CLP) were increased in the absence of intracellular IL-15 in MCs. They also demonstrated that LPS could stimulate MCs to produce more IL-15 and store IL-15 intracellularly. They then found that IL-15 could inhibit the activation of neutrophil-attracting chemokines by downregulating MCs protease expression and activities. Further, by testing with a variety of protease inhibitors and using promoter activity assay, they showed that IL-15 selectively downregulated the activity of a chymase, MCP-2 (mast cell protease-2), by blockingmcpt2 transcription. These findings suggested that MCs IL-15 might restrict MC-dependent antibacterial innate immune responses by suppressing the activity of MCP-2. These data imply that IL-15 may be used as a new treatment for sepsis.

References：

1. Malaviya R. and Abraham S.N. Mast cell modulation of immune responses to bacteria. Immunol. Rev. 179:16–24 (2001)

2. Fehniger T.A. and Caligiuri M.A. Interleukin-15: biology and relevance to human disease. Blood 97, 14-32 (2001)

3. Galli S.J. et al. Mast cells as ‘tunable’ effector and immunoregulatory cells: recent advances. Annu. Rev. Immunol. 23, 749-786 (2005)