Oncostatin M transforms lymphoid tissue function in transgenic mice by stimulating lymph node T-cell development and thymus autoantibody production.
Oncostatin M (OM) is a member of the IL-6 subfamily of cytokines that is expressed in primary lymphoid tissues such as bone marrow and thymus, as well as in secondary lymphoid tissues and activated leukocytes. We produced transgenic mice that overexpressed the human, bovine, or mouse OM genes and compared their relative ability to modulate lymphopoiesis. Each species of cytokine induced a similar extrathymic pathway of T-cell development involving the accumulation of immature T cells within lymph nodes. Reconstitution experiments utilizing lethally irradiated athymic mice indicated that OM had caused hematopoietic precursors within fetal liver and bone marrow to initiate lymph node T-cell development in the absence of a thymic environment. Breeding experiments with IL6-/- and IL-7r(alpha)-/- deficient mice, indicated that induction of this extrathymic pathway by the OM transgene occurred in the absence of IL-6, but was strictly dependent on IL-7 receptor signaling. Separately, OM stimulated the accumulation of immature B cells within the transgenic thymus and caused the subcapsular regions of the thymus to expand with mature B and T cells. This thymus conversion to secondary lymphoid tissue was responsible for a lethal autoimmune-like disease marked by high titers of circulating autoantibodies, proteinuria, and glomerulonephritis. The conserved phenotypes elicited by these three forms of OM indicate that this potent hematopoietic cytokine can regulate lymphoid tissue function and morphogenesis.
Clegg
C H
CH
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA, USA. cleggc@zgi.com
Haugen
H S
HS
Rulffes
J T
JT
Friend
S L
SL
Farr
A G
AG
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001323:Autoantibodies / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D002417:Cattle; D016207:Cytokines / Q000235:genetics; D006131:Growth Inhibitors / Q000235:genetics*; D006801:Humans; D016130:Immunophenotyping; D015850:Interleukin-6 / Q000235:genetics; D015851:Interleukin-7 / Q000235:genetics; D008198:Lymph Nodes / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D008822:Mice, Transgenic; D053683:Oncostatin M; D010455:Peptides / Q000235:genetics*; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology*; D019076:Transgenes
D015703:Antigens, CD; D001323:Autoantibodies; D016207:Cytokines; D006131:Growth Inhibitors; D015850:Interleukin-6; D015851:Interleukin-7; C508351:OSM protein, human; C508352:Osm protein, mouse; D010455:Peptides; D053683:Oncostatin M