Interleukin-6 is required in vivo for the regulation of stem cells and committed progenitors of the hematopoietic system

Bernad, António; Köpf, Manfred; Kulbacki, Robert; Weich, Nadine; Koehler, Georges; Gutierrez‐Ramos, José Carlos

doi:10.1016/s1074-7613(94)80014-6

Cited by 206 publications

(133 citation statements)

References 32 publications

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“…Furthermore, IL-6 is able to support emergency granulopoiesis in animals that simultaneously lack G-CSF and GM-CSF (66). Conversely, deletion of IL-6 in mice leads to abnormal numbers of committed progenitors and an altered recovery after hematopoietic ablation (67). We have found that Lyndeficient mice have increased numbers of myeloid progenitors and EMH that progressively increases with the age and autoimmune disease state of the mice.…”

Section: Discussionmentioning

confidence: 78%

Autoimmune Disease in Lyn-Deficient Mice Is Dependent on an Inflammatory Environment Established by IL-6

Tsantikos

Oracki

Quilici

et al. 2009

The Journal of Immunology

122

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Lyn-deficient mice develop Ab-mediated autoimmune disease resembling systemic lupus erythematosus where hyperactive B cells are major contributors to pathology. In this study, we show that an inflammatory environment is established in Lyn−/− mice that perturbs several immune cell compartments and drives autoimmune disease. Lyn−/− leukocytes, notably B cells, are able to produce IL-6, which facilitates hyperactivation of B and T cells, enhanced myelopoiesis, splenomegaly, and, ultimately, generation of pathogenic autoreactive Abs. Lyn−/− dendritic cells show increased maturation, but this phenotype is independent of autoimmunity as it is reiterated in B cell-deficient Lyn−/− mice. Genetic deletion of IL-6 on a Lyn-deficient background does not alter B cell development, plasma cell accumulation, or dendritic cell hypermaturation, suggesting that these characteristics are intrinsic to the loss of Lyn. However, hyperactivation of B and T cell compartments, extramedullary hematopoiesis, expansion of the myeloid lineage and autoimmune disease are all ameliorated in Lyn−/−IL-6−/− mice. Importantly, our studies show that although Lyn−/− B cells may be autoreactive, it is the IL-6–dependent inflammatory environment they engender that dictates their disease-causing potential. These findings improve our understanding of the mode of action of anti–IL-6 and B cell-directed therapies in autoimmune and inflammatory disease treatment.

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Section: Discussionmentioning

confidence: 78%

Autoimmune Disease in Lyn-Deficient Mice Is Dependent on an Inflammatory Environment Established by IL-6

Tsantikos

Oracki

Quilici

et al. 2009

The Journal of Immunology

122

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“…IL-6 supports HPC proliferation, 28,29,58,59 and we have recently shown it to be a critical regulator of PTH actions in HPC expansion. 13 Because the calvarial organ is composed primarily of stromal osteoblastic cells, the predominant PPR-expressing cell population in the bone marrow, the more significantly increased PTH-induced IL-6 mRNA in Prg4 mutant calvaria suggests that a stromal osteoblastic cell is the target of PTH actions to modulate IL-6 and hematopoietic cells in the marrow of Prg4 mutant mice.…”

Section: Discussionmentioning

confidence: 98%

Proteoglycan 4, a Novel Immunomodulatory Factor, Regulates Parathyroid Hormone Actions on Hematopoietic Cells

Novince¹,

Koh²,

Michalski³

et al. 2011

The American Journal of Pathology

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Proteoglycan 4 (PRG4), a critical protective factor in articular joints, is implicated in hematopoietic progenitor cell expansion and megakaryopoiesis. PRG4 loss-of-function mutations result in camptodactyly-arthropathy-coxa varapericarditis (CACP) syndrome, which is characterized primarily by precocious joint failure. PRG4 was identified as a novel parathyroid hormone (PTH) responsiveness gene in osteoblastic cells in bone, and was investigated as a potential mediator of PTH actions on hematopoiesis. Sixteen-week-old Prg4 ؊/؊ mutant and Prg4 ؉/؉ wild-type mice were treated daily with intermittent PTH (residues 1-34) or vehicle for 6 weeks. At 22 weeks of age, Prg4 mutant mice had increased peripheral blood neutrophils and decreased marrow B220 ؉ (B-lymphocytic) cells, which were normalized by PTH. The PTH-induced increase in marrow Lin ؊ Sca-1 ؉ c-Kit ؉ (hematopoietic progenitor) cells was blunted in mutant mice. Basal and PTHstimulated stromal cell-derived factor-1 (SDF-1) was decreased in mutant mice, suggesting SDF-1 as a candidate regulator of proteoglycan 4 actions on hematopoiesis in vivo. PTH stimulation of IL-6 mRNA was greater in mutant than in wild-type calvaria and bone marrow, suggesting a compensatory mechanism in the PTH-induced increase in marrow hematopoietic progenitor cells. In summary, proteoglycan 4 is a novel PTH-responsive factor regulating immune cells and PTH actions on marrow hematopoietic progenitor cells.

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“…Furthermore, they found fewer than normal day 12 spleen (CFU-S) in IL-6 Ϫ/Ϫ bone marrow and spleen, as well as fewer pre-CFU-S in IL-6 Ϫ/Ϫ bone marrow. The ability of the IL-6 Ϫ/Ϫ long-term repopulating stem cell compartment (which reflects the activity of hemopoietic stem cells) to reconstitute irradiated mice was adequate initially, but diminished with successive transplantation, implying a defect in its self-renewal ability (32). Given that we found increased and sustained BMDC generation from IL-6 Ϫ/Ϫ bone marrow, it appears that any potential deficits in the quantity of committed progenitors or function of stem cells in IL-6 Ϫ/Ϫ mice are overcome by culture in GM-CSF.…”

Section: Discussionmentioning

confidence: 99%

Increased and Long-Term Generation of Dendritic Cells with Reduced Function from IL-6-Deficient Bone Marrow

Bleier

Pillarisetty

Shah

et al. 2004

The Journal of Immunology

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The importance of IL-6 in dendritic cell (DC) development and function has not been well defined. To establish the role of IL-6, we studied bone marrow-derived DC (BMDC) and freshly isolated splenic DC from IL-6−/−-transgenic mice. We found that although IL-6−/− bone marrow had a similar composition to that of wild-type (WT) mice, it generated up to 10 times more DC when cultured in GM-CSF. The difference persisted even when IL-6−/− and WT bone marrow were cultured together, excluding the possibility that the effects were simply due to different cytokine microenvironments. In comparison to WT BMDC, IL-6−/− BMDC captured at least as much Ag, had an equivalent surface phenotype, and matured similarly in response to LPS or CpG. However, IL-6−/− BMDC induced less T cell allostimulation and Ag-specific T cell activation, but only the former was related to their inability to generate IL-6. Although WT bone marrow cultures died within 4 wk, IL-6−/− cultures continued to generate BMDC for >120 days, although the BMDC became immature and less functional. In vivo, we found that IL-6−/− mice had similar numbers and types of splenic DC as WT mice, both normally and after treatment with either Flt-3 ligand or GM-CSF. These findings demonstrate that IL-6 has profound effects on DC development in vitro, although the number and subtype composition of DC are unaffected by the absence of IL-6 in vivo. Furthermore, secretion of IL-6 is critical to certain DC functions.

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Interleukin-6 is required in vivo for the regulation of stem cells and committed progenitors of the hematopoietic system

Cited by 206 publications

References 32 publications

Autoimmune Disease in Lyn-Deficient Mice Is Dependent on an Inflammatory Environment Established by IL-6

Autoimmune Disease in Lyn-Deficient Mice Is Dependent on an Inflammatory Environment Established by IL-6

Proteoglycan 4, a Novel Immunomodulatory Factor, Regulates Parathyroid Hormone Actions on Hematopoietic Cells

Increased and Long-Term Generation of Dendritic Cells with Reduced Function from IL-6-Deficient Bone Marrow

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