Roles of CXC chemokines and macrophages in the recruitment of inflammatory cells and tumor rejection induced by Fas/Apo-1 (CD95) ligand-expressing tumor.
The role of CD95 ligand (FasL/Apo-1L)-expressing tumors in immunosuppression or immunopotentiation is controversial. CD95L-transfected tumors induce immunopotentiation after vigorous neutrophil infiltration. Thus, the induction of neutrophil infiltration by CD95L seems to play an important role in tumor rejection. The mechanism by which CD95L-expressing tumors cause neutrophil infiltration and antitumor immunity has not been well understood. CXC chemokine receptor 2 (CXCR2) knockout (KO) mice are a powerful tool for studying CXC chemokine-mediated neutrophil infiltration. We investigated the roles of CD95L and chemokines in CD95L-induced antitumor activity by using CXCR2 KO mice and CD95LcDNA-transfected MethA (MethA + CD95L) fibrosarcoma. MethA + CD95L cells were completely rejected in wild-type (WT) and even in KO mice. MethA + CD95L cells injected intraperitoneally (i.p.) induced the recruitment of both neutrophils and macrophages in WT but only macrophages in KO mice, although CXC and CC chemokines were released in both mice. Macrophages incubated with MethA + CD95L cells released CXC and CC chemokines. Macrophages derived from WT and KO but not neutrophils from WT mice induced the recruitment of neutrophils when adoptively i.p. transferred with MethA + CD95L cells into CD95L/CD95-deficient mice. The different recruitment of inflammatory cells between WT and KO mice was attributed to bone marrow (BM) cells by BM transfer experiment. Our results demonstrated that CXC chemokines are essential for neutrophil recruitment and that macrophages but not neutrophils play a critical role in the CD95L-induced infiltration of inflammatory cells and the eradication of CD95L-expressing tumor cells.
Shimizu
Motomu
M
Medical R&D Center, Tokyo Metropolitan Institute of Medical Science, Tokyo Metropolitan Organization for Medical Research, Bunkyo-ku, Tokyo 113-8613, Japan. shimizu@rinshoken.or.jp
Yoshimoto
Takayuki
T
Sato
Mayumi
M
Morimoto
Junji
J
Matsuzawa
Akio
A
Takeda
Yasutaka
Y
D000818:Animals; D019743:Chemokines, CXC / Q000276:immunology* / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D053222:Fas Ligand Protein; D005354:Fibrosarcoma / Q000473:pathology* / Q000662:veterinary; D005434:Flow Cytometry; D008264:Macrophages / Q000276:immunology*; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D012333:RNA, Messenger / Q000032:analysis; D019014:fas Receptor / Q000276:immunology*
D019743:Chemokines, CXC; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D019014:fas Receptor