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Published online before print June 18, 2007

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(Journal of Leukocyte Biology. 2007;82:721-728.)
© 2007 by Society for Leukocyte Biology

Fas (CD95) induces macrophage proinflammatory chemokine production via a MyD88-dependent, caspase-independent pathway

William A. Altemeier^*,1,2, Xiaodong Zhu^*,2, William R. Berrington^*, John M. Harlan^* and W. Conrad Liles^*,

^* Department of Medicine, University of Washington School of Medicine, Seattle, Washington, USA; and
Department of Medicine, Toronto General Research Institute, McLaughlin-Rotman Centre for Global Health, McLaughlin Centre for Molecular Medicine, University of Toronto, Toronto, Ontario, Canada

¹ Correspondence: Box 356522, University of Washington, 1959 NE Pacific St., Seattle, WA 98105-6522, USA. E-mail: billa{at}u.washington.edu

Activation of the prototypical death receptor, Fas (CD95), can induce both caspase-dependent cell death and production of proinflammatory chemokines, leading to neutrophil recruitment and end-organ injury. The precise mechanism(s) by which Fas up-regulates chemokine production and release, is currently unclear. We hypothesized that Fas-induced chemokine release by macrophages is dependent on the MyD88 adaptor molecule and independent of caspase activity. To test this hypothesis, we measured chemokine response to Fas activation both in RAW 264.7 cells with RNAi-attenuated MyD88 expression and in MyD88-deficient primary macrophages. We found that Fas-induced chemokine release was abrogated in the absence of MyD88. In vivo, MyD88^–/– mice had impaired CXCL1/KC release and polymorphonuclear cell recruitment in response to intratracheal treatment with the Fas-activating monoclonal antibody, Jo-2. Furthermore, Fas-induced chemokine release was not dependent on either IL-1 receptor signaling or on caspase activity. We conclude that MyD88 plays an integral role in Fas-induced macrophage-mediated inflammation.

Key Words: inflammation • apoptosis • lung injury • neutrophil

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