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Pneumocystis ‐mediated IL‐8 release by macrophages requires coexpression of mannose receptors and TLR2
Author(s) -
Tachado Souvenir D.,
Zhang Jianmin,
Zhu Jinping,
Patel Naimish,
Cushion Melanie,
Koziel Henry
Publication year - 2007
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.1005580
Subject(s) - biology , tlr2 , hek 293 cells , receptor , transfection , mannose receptor , microbiology and biotechnology , innate immune system , gene silencing , cell culture , macrophage , biochemistry , in vitro , gene , genetics
Interaction with the unique fungus Pneumocystis (Pc) promotes IL‐8 release by human alveolar macrophages (AM), although the receptor(s) mediating IL‐8 release have not been identified. TLR2 recognizes fungal components and mediates release of host defense cytokines and chemokines, although whether TLR2 mediates signaling in response to Pc is not known. In the current study, Pc induced IL‐8 release by human AM, and AM pretreatment with anti‐TLR2 neutralizing antibody reduced IL‐8 release. However, in nonphagocytic human embryonic kidney (HEK)293 cells transfected with human TLR2 cDNA, incubation with Pc did not induce IL‐8 release, whereas these same cells released IL‐8 in response to the TLR2 agonist lipoteichoic acid. Targeted gene silencing of AM mannose receptors (MR; phagocytic receptors for Pc) using small interfering RNA also reduced Pc‐mediated IL‐8 release in human AM. However, HEK293 cells transfected with human MR cDNA alone did not release IL‐8 in response to Pc. In contrast, HEK293 cells cotransfected with human TLR2 and human MR cDNA released IL‐8 in response to Pc. In human AM, Pc promoted direct interaction of MR and TLR2, IL‐8 release was reduced markedly upon simultaneous blocking of TLR2 and gene silencing of MR, and IL‐8 release was dependent in part on transcription factor NF‐κB and ERK1/2 and JNK MAPKs. These studies demonstrate that Pc‐mediated IL‐8 release by human AM requires the coexpression of MR and TLR2 and further supports the concept that combinatorial interactions of macrophage innate receptors provide specificity of host defense cell responses to infectious challenge.