title: Activated expression of the chemokine Mig after chemotherapy contributes to chemotherapy-induced bone marrow suppression and lethal toxicity.
abstract: Alterations in gene expression after chemotherapy may potentially help to identify mediators that induce suppression or regeneration in bone marrow. This paper reports our observation that the expression of the chemokine monokine induced by IFN-γ (Mig) and its receptor CXCR3 was significantly activated in mice after treatment with the chemotherapeutic agent 5-fluorouracil (5-FU). The neutralization of antibodies against the activated Mig increased the survival rate and accelerated BM recovery after chemotherapy. In addition, elevation of Mig plasma levels after 5-FU treatment corresponded with increased mortality. The cell cycle-inhibiting effect of the prophylactic administration of Mig protected hematopoietic progenitor cells (HPCs) from 1-β-d-arabinofuranosylcytosine in spleen colony assays and enhanced the irradiated recipients' survival. In CXCR3(-/-) mice, Mig did not propagate BM suppression, indicating that the suppressive effect of Mig is dependent on CXCR3. On the one hand, Mig stimulated p70 S6K and Erk1/2 pathways in mesenchymal stroma cells, inhibiting mesenchymal stroma cell-dependent HPC expansion. Moreover, Mig suppressed the STAT5 pathway in HPCs, inhibiting leukocyte differentiation. Our results strongly suggest that Mig contributes to the acute lethal toxicity arising from 5-FU administration. Neutralization of Mig may offer new strategies to alleviate BM toxicity with potentially dramatic implications for chemotherapy.
authors.affiliation: Laboratory of Regeneromics, School of Pharmacy, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Huili
authors.initials: H
authors.lastname: Lu
authors.forename: Shunying
authors.initials: S
authors.lastname: Zhu
authors.forename: Lan
authors.initials: L
authors.lastname: Qian
authors.forename: Di
authors.initials: D
authors.lastname: Xiang
authors.forename: Wu
authors.initials: W
authors.lastname: Zhang
authors.forename: Aifang
authors.initials: A
authors.lastname: Nie
authors.forename: Jin
authors.initials: J
authors.lastname: Gao
authors.forename: Mingyuan
authors.initials: M
authors.lastname: Wu
authors.forename: Jinming
authors.initials: J
authors.lastname: Gao
authors.forename: Bao
authors.initials: B
authors.lastname: Lu
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.forename: Wei
authors.initials: W
authors.lastname: Han
authors.forename: Anja
authors.initials: A
authors.lastname: Moldenhauer
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000473:pathology; D002478:Cells, Cultured; D054370:Chemokine CXCL9 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D064420:Drug-Related Side Effects and Adverse Reactions / Q000235:genetics / Q000401:mortality* / Q000517:prevention & control; D005472:Fluorouracil / Q000009:adverse effects / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D007108:Immune Tolerance / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis; D051381:Rats; D017208:Rats, Wistar; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D054370:Chemokine CXCL9; D018925:Chemokines; C485969:Cxcl9 protein, mouse; D005472:Fluorouracil