Constitutive expression of IL-6-LIKE cytokines in normal bone marrow: implications for pathophysiology of myeloma.
Myeloma is a neoplasm thought to "home" to bone marrow. However, evidence for bone-marrow-specific receptors or adhesion molecules expressed on myeloma cells is scanty. Initial myeloma expansion is thought to be due to IL-6 and/or related cytokines. Previous determinations of cytokine expression in bone marrow were performed on bone marrow stromal lines; these findings may not reflect the constitutive pattern of expression in situ. Intracytoplasmic staining for IL-6-like cytokines revealed constitutive expression of some factors in the bone marrow of normal mice, but not spleens. Spleens of myeloma-transplanted SCID mice expressed IL-6-like cytokines, indicative of induction of expression by myeloma. Some cytokines expressed in bone marrow induced myeloma proliferation in the presence of dexamethasone, demonstrating dependence of the myeloma on these cytokines. Our data imply that, rather than "homing" to bone marrow, myeloma cells proliferated within marrow cavities more than in other organs because of growth factors constitutively expressed by bone marrow cells. As myeloma progressed, we observed the induction of growth factor expression in spleen cells. Furthermore, because cytokines other than IL-6 may induce myeloma cell proliferation, therapy aimed at neutralizing IL-6 may not be the most effective method to treat this disease. These findings have implications for both the pathophysiology and therapy of multiple myeloma.
Barton
B E
BE
Department of Surgery, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, 185 S. Orange Avenue, Newark, New Jersey 07103, USA. bartonbe@umdnj.edu
Murphy
T F
TF
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001853:Bone Marrow / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D002469:Cell Separation; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D017370:Interleukin-11 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis*; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000096:biosynthesis; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000378:metabolism* / Q000503:physiopathology*; D009368:Neoplasm Transplantation; D053683:Oncostatin M; D010455:Peptides / Q000494:pharmacology; D013154:Spleen / Q000378:metabolism; D014407:Tumor Cells, Cultured
D018931:Antineoplastic Agents, Hormonal; D006131:Growth Inhibitors; D017370:Interleukin-11; D015850:Interleukin-6; C507837:LIF protein, human; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; C508351:OSM protein, human; C508352:Osm protein, mouse; D010455:Peptides; D053683:Oncostatin M; D003907:Dexamethasone