IL-6 increases B-cell IgG production in a feed-forward proinflammatory mechanism to skew hematopoiesis and elevate myeloid production

Maeda, Kenichiro; Mehta, Harshini; Drevets, Douglas A.; Coggeshall, K. Mark

doi:10.1182/blood-2009-07-230631

Cited by 122 publications

(91 citation statements)

References 70 publications

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“…We also demonstrated that tumor cells are capable of stimulating such modified Th2 responses, featuring production of IL-10 and IL-4 and secretion of IgG4 by B cells. Also consistent with a tumor-associated inflammatory environment, VEGF, known to polarize Th2-biased cytokine production by PBMCs through induction of IL-10-secreting cells such as Tregs (53), along with well-described tumor-induced inflammatory mediators IL-6 and MCP-1 (53)(54)(55)(56), was found at significantly increased levels (P < 0.001; Supplemental Figure 3A Figure 8. n = 33.…”

Section: Discussionmentioning

confidence: 59%

IgG4 subclass antibodies impair antitumor immunity in melanoma

Karagiannis

Gilbert²,

Josephs³

et al. 2013

J. Clin. Invest.

181

211

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Section: Discussionmentioning

confidence: 59%

IgG4 subclass antibodies impair antitumor immunity in melanoma

Karagiannis

Gilbert²,

Josephs³

et al. 2013

J. Clin. Invest.

181

211

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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 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). At a young age, SHIP-1 2/2 mice develop an inflammatory lung disease accompanied by M2 macrophage polarization reflected in chitinase crystal accumulation in alveolar macrophages and in lungs (3,4,9,10).…”

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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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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“…However IL-6 is not directly associated with the immunoinhibitory activity UC-MSC on CD4 + T cell [39]. IL-6 was originally isolated and cloned as a B-cell differentiation factor that induced terminal B-cell differentiation and supported the production of immunoglobulin G (IgG) [40,41] We observed that although the level of IL-6 was higher in coculture system, the neutralizing antibodies to IL-6 did not affect the immunomodulation on B cells. In conclusion, we presumed that IL-6 does not participate in the immunoinhibitory activity of UC-MSC on B cells.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal Stem Cells Support Proliferation and Terminal Differentiation of B Cells

Zhou

Han

et al. 2012

Cell Physiol Biochem

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Background: Mesenchymal stem cells (MSC) play important roles in modulating the activities of T lymphocytes, dendritic cells and natural killer cells. These immunoregulatory properties of MSC suggest their therapeutic potential in autoimmune diseases. However, the effects of MSC on B cells are still poorly understood. The present study was designed to investigate the interaction between MSC and B cells both in vitro and in vivo, and to determine the possible mechanism of action. Design and Method: The effect of human umbilical cord mesenchymal stem cells (UC-MSC) on proliferation and differentiation of B-cells were characterized in vitro, and we also tested the immunoregulatory properties of mouse bone marrow MSC (BM-MSC) on T cell dependent and independent antibody production in vivo in mice. Results: Treatment with human UC-MSC resulted in an increase of proliferation, differentiation of B cells into plasma cells and production of antibodies in vitro. Mouse BM-MSC significantly enhanced T cell dependent and independent antibodies production in vivo in mice. PGE2 partially mediated the immunosuppressive activity of human UC-MSC but IL-6 did not regulate this activity. Conclusion: MSC promote proliferation and differentiation of B cells in vitro and in vivo partially through PGE2 but not IL-6.

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IL-6 increases B-cell IgG production in a feed-forward proinflammatory mechanism to skew hematopoiesis and elevate myeloid production

Cited by 122 publications

References 70 publications

IgG4 subclass antibodies impair antitumor immunity in melanoma

IgG4 subclass antibodies impair antitumor immunity in melanoma

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

Mesenchymal Stem Cells Support Proliferation and Terminal Differentiation of B Cells

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