Involvement of Interleukin (IL) 8 receptor in negative regulation of myeloid progenitor cells in vivo: evidence from mice lacking the murine IL-8 receptor homologue.
Expansion of mature neutrophils has been observed in mice lacking the murine interleukin (IL) 8 receptor homolog [mIL-8Rh(-/-)], and human (hu) IL-8 suppresses proliferation of primitive myeloid cells in vitro and in vivo. To evaluate involvement and relevance of murine IL-8 receptor homolog (mIL-8Rh) in negative regulation of myelopoiesis, we studied mIL-8Rh(-/-) and (+/+) mice raised in a normal or germ-free environment. Immature myeloid progenitors from mIL-8Rh(+/+) mice bred under normal or germ-free conditions were significantly suppressed in vitro by recombinant huIL-8, macrophage inflammatory protein (MIP)-1 alpha, platelet factor (PF) 4, interferon inducible protein (IP) 10, monocyte chemotactic peptide (MCP) 1, and H-ferritin. In contrast, progenitors from mIL-8Rh(-/-) mice were insensitive to inhibition by IL-8, but not to these other chemokines and H-ferritin. Mouse MIP-2, a ligand for mIL-8Rh, suppressed progenitors from normal but not mIL-8Rh(-/-) mice. Under normal environmental conditions, enhanced numbers of myeloid progenitors were found in femur, spleen, and blood of mIL-8Rh(-/-) compared with mIL-8Rh(+/+) mice. Numbers of myeloid progenitors were greatly decreased in mIL-8Rh(-/-)and (+/+) mice in germ-free conditions, and were either not significantly enhanced in mIL-8Rh(-/-) mice compared with (+/+) mice or were only moderately so. Differences in progenitors/organ between a germ-free and normal environment were greater for the mIL-8Rh(-/-) mice. These results document selective insensitivity of myeloid progenitor cells from mIL-8Rh(-/-) mice to inhibition by huIL-8 and mouse MIP-2 and a large expansion of myeloid progenitors in these mice, the latter effect being environmentally inducible. This provides strong support for a negative myeloid regulatory role played by the mIL-8Rh in vivo, whose active ligand may be MIP-2.
Broxmeyer
H E
HE
Department of Medicine (Hematology/Oncology), Indiana University School of Medicine, Indianapolis 46202, USA.
Cooper
S
S
Cacalano
G
G
Hague
N L
NL
Bailish
E
E
Moore
M W
MW
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D001854:Bone Marrow Cells; D002454:Cell Differentiation; D018932:Chemokine CCL2 / Q000494:pharmacology; D018946:Chemokine CCL5 / Q000494:pharmacology; D054357:Chemokine CXCL10; D018925:Chemokines / Q000494:pharmacology*; D019743:Chemokines, CXC; D016207:Cytokines / Q000494:pharmacology; D005856:Germ-Free Life; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000502:physiology*; D006965:Hyperplasia; D016209:Interleukin-8 / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D010978:Platelet Factor 4 / Q000494:pharmacology; D018123:Receptors, Interleukin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D023062:Receptors, Interleukin-8A; D013154:Spleen / Q000166:cytology
D015703:Antigens, CD; D018932:Chemokine CCL2; D018946:Chemokine CCL5; D054357:Chemokine CXCL10; D018925:Chemokines; D019743:Chemokines, CXC; D016207:Cytokines; D016209:Interleukin-8; D019402:Macrophage Inflammatory Proteins; D018123:Receptors, Interleukin; D023062:Receptors, Interleukin-8A; D010978:Platelet Factor 4