IL-6 blocks a discrete early step in lymphopoiesis

Maeda, Kengo; Baba, Yoshifumi; Nagai, Yoshinori; Miyazaki, Kentaro; Malykhin, Alexander; Nakamura, Koji; Kincade, Paul W.; Sakaguchi, Nobuo; Coggeshall, K. Mark

doi:10.1182/blood-2005-02-0456

Cited by 87 publications

(79 citation statements)

References 36 publications

(43 reference statements)

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“…This finding was unexpected and now questions the true nature of the lung disease in SHIP-1 2/2 mice, and suggests that the M2 classification of this disorder is not strictly correct. IL-6 is elevated in serum and BAL of C57.SHIP-1 2/2 mice (6,8,10,31). It is well known to influence hematopoietic progenitor number and myelopoiesis: injection of IL-6 into mice can induce myelopoiesis and myeloproliferative disease (32), and IL-6 can synergize with other cytokines to drive production of immature hematopoietic progenitors (33,34 (20,(37)(38)(39)(40)(41)(42), and there is evidence that the 129 strain is autoimmune prone (43,44).…”

Section: Discussionmentioning

confidence: 99%

“…SHIP-1 2/2 mice develop splenomegaly with an expansion of erythroid and myeloid cells, and their progenitors (1)(2)(3), and SHIP-1 2/2 hematopoietic cells are hyperresponsive to GM-CSF (3,4). SHIP-1 2/2 mice show an increase in circulating IL-6, which is thought to suppress lymphopoiesis and promote myelopoiesis (5,6). Recently, macrophages and dendritic cells from SHIP-1 2/2 mice have been implicated as the IL-6-overproducing cells (7,8).…”

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confidence: 99%

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Genetic Segregation of Inflammatory Lung Disease and Autoimmune Disease Severity in SHIP-1−/− Mice

Maxwell

Duan

Armes

et al. 2011

The Journal of Immunology

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Alternatively activated M2 macrophages are implicated as both regulators and agents of lung disease, but their control is poorly understood. SHIP-1 is a 5′ inositol phosphatase that negatively regulates the PI3K signaling pathway implicated in inflammation. SHIP-1–deficient mice have defects in hematopoiesis and B cell development, and die prematurely due to consolidation of lungs with M2-skewed macrophages. SHIP-1 is thought to restrain M2 macrophage polarization, with deregulated M2 skewing coinciding with severe lung disease in SHIP-1–deficient mice. To determine the influence of genetic background on the lung phenotype in SHIP-1−/− mice, we backcrossed the SHIP-1 null mutation onto C57BL/6 (Th2-resistant) and BALB/c (Th2-prone) backgrounds. Remarkably, we found that inflammatory lung disease was severe in C57.SHIP-1−/− mice, but absent in BALB.SHIP-1−/− mice. C57.SHIP-1−/−, but not BALB.SHIP-1−/− mice had greatly increased myeloid progenitors, myeloid hyperplasia, markedly enhanced numbers of activated alveolar macrophages, and elevated amounts of Th2 and proinflammatory cytokines in bronchoalveolar lavage fluid and serum, suggesting that deregulated cytokine production induced disease. C57.SHIP-1−/− mice also developed severe B cell-dependent autoimmune disease, which was markedly attenuated on the BALB/c background. These data demonstrate that, contrary to current concepts, loss of SHIP-1 alone is not sufficient to cause lung inflammation, with disease only manifest on a permissive genetic background. This finding questions the nature of the lung disease in SHIP-1−/− mice, suggesting that its M2 classification is not strictly correct. Future identification of disease-promoting loci might reveal determinants of comorbid lung disease and autoimmunity and uncover potentially useful therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Genetic Segregation of Inflammatory Lung Disease and Autoimmune Disease Severity in SHIP-1−/− Mice

Maxwell

Duan

Armes

et al. 2011

The Journal of Immunology

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“…The heavy infiltration by T and Mac1 + cells observed in the BM and lymphoid organs led us to conclude that suppression of HSC-derived hematopoiesis was mediated by alloreactive T cells that homeostatically expanded and induced a proinflammatory environment. It has been shown that cytokines, such as IL-6, TGFβ, TNFα, and IFNγ, suppress hematopoiesis by blocking lineage commitment (29), impairing cell division (30), and inducing programmed cell death (31). Inflammation can also damage the host cellular components of HSC niches (13), making the marrow inhospitable for blood cell production.…”

Section: Discussionmentioning

confidence: 99%

Allogeneic T cells impair engraftment and hematopoiesis after stem cell transplantation

Müller

Linderman

Florek

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Because of the perception that depleting hematopoietic grafts of T cells will result in poorer immune recovery and in increased risk of graft rejection, pure hematopoietic stem cells (HSC), which avoid the potentially lethal complication of graft-versus-host disease (GVHD), have not been used for allogeneic hematopoietic cell transplantation (HCT) in humans. Ideal grafts should contain HSC plus mature cells that confer only the benefits of protection from pathogens and suppression of malignancies. This goal requires better understanding of the effects of each blood cell type and its interactions during engraftment and immune regeneration. Here, we studied hematopoietic reconstitution post-HCT, comparing grafts of purified HSC with grafts supplemented with T cells in a minor histocompatibility antigen (mHA)-mismatched mouse model. Cell counts, composition, and chimerism of blood and lymphoid organs were evaluated and followed intensively through the first month, and then subsequently for up to 1 yr. Throughout this period, recipients of pure HSC demonstrated superior total cell recovery and lymphoid reconstitution compared with recipients of T cell-containing grafts. In the latter, rapid expansion of T cells occurred, and suppression of hematopoiesis derived from donor HSC was observed. Our findings demonstrate that even early post-HCT, T cells retard donor HSC engraftment and immune recovery. These observations contradict the postulation that mature donor T cells provide important transient immunity and facilitate HSC engraftment.immune reconstitution | graft composition | mice

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“…19,20 Our earlier work established that the changes in hematopoiesis of SHIP Ϫ/Ϫ mice are caused by IL-6 because the increased myeloid output from uncommitted progenitors in this model was blocked by neutralizing antibodies to 20 and CD19 ϩ B lymphopoiesis was restored in SHIP Ϫ/Ϫ IL-6 Ϫ/Ϫ double-deficient mice. 19 Remarkably, IL-6 is able to support emergency granulopoiesis in animals that lack granulocyte colony-stimulating factor and granulocyte-macrophage colony stimulating factor, 21 2 critical cytokines necessary for myelopoiesis. 22 These findings indicate that IL-6 plays a key role in emergency granulopoiesis that accompanies acute infections.…”

mentioning

confidence: 90%

Interleukin-6 aborts lymphopoiesis and elevates production of myeloid cells in systemic lupus erythematosus–prone B6.Sle1.Yaa animals

Maeda¹,

Malykhin²,

Teague-Weber

et al. 2009

Blood

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We previously reported the inhibitory action of interleukin-6 (IL-6) on B lymphopoiesis with SHIP ؊/؊ mice and showed that IL-6 biases lineage commitment toward myeloid cell fates in vitro and in vivo. Because elevated IL-6 is a feature of chronic inflammatory diseases, we applied an animal model of systemic lupus erythematosus (SLE) to determine whether IL-6 has similar effects on hematopoiesis. We found that IL-6 levels were elevated in the B6.Sle1.Yaa mice, and the increase was accompanied by losses of CD19 ؉ B cells and more primitive B-lymphoid progenitors in bone marrow. Both the CD19 ؉ B-cell population and their progenitors recovered in an IL-6 ؊/؊ background. The uncommitted progenitors, containing precursors for both lymphoid and myeloid fates, expressed IL-6 receptor-␣ chain and responded to IL-6 by phosphorylation of STAT3. IL-6 stimulation caused uncommitted progenitors to express the Id1 transcription factor, which is known to inhibit lymphopoiesis and elevate myelopoiesis, and its expression was MAPK dependent. We conclude that chronic inflammatory conditions accompanied by increased IL-6 production bias uncommitted progenitors to a myeloid fate by inducing Id1 expression. IntroductionAll hematopoietic cells develop from pluripotent hematopoietic stem cells (HSCs). Hematopoietic development proceeds in stages of decreasing lineage choices and decreasing capacity for selfrenewal of the progeny. HSCs feature a lack of all lineage markers (Lin Ϫ ) but express high levels of the receptor tyrosine kinase c-Kit (c-Kit hi ) and the surface protein Sca-1 (termed the LSK fraction). HSCs give rise to multipotent progenitors (MPPs), marked by a loss of self-renewal capacity, the ability to form either myeloid or lymphoid cells, and up-regulation of the Flk2/Flt3 receptor tyrosine kinase. 1 The earliest lymphoid-biased progenitors (ELPs) represent a subset of MPPs that can be resolved from all other progenitors on the basis of recombination activating gene 1 expression. 2 Lymphoid progenitors that develop from MPPs have reduced levels of c-Kit, display surface interleukin-7 receptor ␣ (IL-7R␣), and have other properties that define a population called common lymphoid progenitors (CLPs). 3 Hematopoiesis is normally a well-controlled system designed to replenish blood cells at a constant rate, such that the balance of lymphoid and myeloid cells is maintained. However, the rate of output of particular blood cell types can be altered by conditions such as leukemia, radiation, or acute inflammation. 4-11 One condition termed "emergency hematopoiesis," 12,13 is characterized by elevated production of myeloid cells, occurring during acute infections or acute allergic responses. The mechanism by which hematopoiesis is altered to elevate production of myeloid cells is not known. The consequence of emergency hematopoiesis is to increase circulating monocytes, granulocytes, and neutrophils, presumably present to fight infection.Interleukin-6 (IL-6) is a prominent cytokine produced during infectious disease (reviewed in...

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IL-6 blocks a discrete early step in lymphopoiesis

Cited by 87 publications

References 36 publications

Genetic Segregation of Inflammatory Lung Disease and Autoimmune Disease Severity in SHIP-1−/− Mice

Genetic Segregation of Inflammatory Lung Disease and Autoimmune Disease Severity in SHIP-1−/− Mice

Allogeneic T cells impair engraftment and hematopoiesis after stem cell transplantation

Interleukin-6 aborts lymphopoiesis and elevates production of myeloid cells in systemic lupus erythematosus–prone B6.Sle1.Yaa animals

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