Stimulation of the molecule 4-1BB enhances host defense against Listeria monocytogenes infection in mice by inducing rapid infiltration and activation of neutrophils and monocytes.
The tumor necrosis factor receptor family molecule 4-1BB (CD137) has diverse roles in adaptive and innate immune responses. However, little is known of its role in bacterial infections. Previously, we showed that 4-1BB-deficient mice have enhanced susceptibility to Listeria monocytogenes infection, and mice pretreated with agonistic anti-4-1BB antibody (3E1) were much more resistant to L. monocytogenes infection than mice treated with control antibody. In this study, we report that stimulating 4-1BB by administering 3E1 in the early phase of L. monocytogenes infection is critical for promoting the survival of mice by inducing rapid infiltration of neutrophils and monocytes into L. monocytogenes-infected livers. The levels of tumor necrosis factor alpha, interleukin 6, and monocyte chemoattractant protein 1 in the livers of 3E1-treated mice increased as early as 30 min postinfection and peaked by 1 to 2 h, while those in mice treated with control antibody started to increase only at 16 h postinfection. Monocytes and neutrophils from the 3E1-treated mice had higher levels of activation markers, phagocytic activity, and reactive oxygen species than those from control mice. In vitro stimulation of 4-1BB induced the production of the inflammatory cytokines/chemokines of neutrophils, but not those of monocytes. These results suggest that 4-1BB stimulation of neutrophils in the early phase of L. monocytogenes infection causes rapid production of inflammatory cytokines/chemokines and that the subsequent infiltration of neutrophils and monocytes is crucial for eliminating the infecting L. monocytogenes.
Lee
Sang-Chul
SC
Department of Biological Sciences, University of Ulsan, San 29, Mookeo-dong, Nam-Ku, Ulsan, Republic of Korea,.
Ju
Seong-A
SA
Sung
Boo-Hee
BH
Heo
Sook-Kyoung
SK
Cho
Hong Rae
HR
Lee
Eun A
EA
Kim
Jung Dae
JD
Lee
In Hee
IH
Park
Sang-Min
SM
Nguyen
Quang Tam
QT
Suh
Jae-Hee
JH
Kim
Byung-Sam
BS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018932:Chemokine CCL2 / Q000032:analysis; D005260:Female; D015850:Interleukin-6 / Q000032:analysis; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology*; D008099:Liver / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D010587:Phagocytosis; D017382:Reactive Oxygen Species / Q000378:metabolism; D016019:Survival Analysis; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000819:agonists* / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D000911:Antibodies, Monoclonal; D018932:Chemokine CCL2; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D014409:Tumor Necrosis Factor-alpha