Interleukin-6 knockout reverses macrophage differentiation imbalance and alleviates cardiac dysfunction in aging mice

Abstract A unique subclone of a bone marrow-derived stromal cell line, BMS2.4, produces soluble factors that inhibit proliferation of several types of hematopoietic cell lines. An understanding of these molecules may be informative about negative regulatory circuits that can potentially limit blood cell formation. We used expression cloning to identify interleukin-6 (IL-6) as one factor that suppressed growth of a pre-B–cell variant line, 1A9-M. Moreover, IL-6 induced macrophage-differentiation and apoptosis of 1A9-M cells. During this process, IL-6 downregulated expression of BCL2 in 1A9-M cells and stimulated BCL-XL expression, but had no effect on p53, Bax, or Bak gene expression. Mechanisms for transduction of IL-6–induced signals were then evaluated in IL-6–stimulated 1A9-M cells. Whereas the signal transducer and activator of transcription 3 (Stat3) was phosphorylated and activated, there was no effect on either Stat1 or Stat5. The importance of BCL2 and Stat3 on IL-6–induced macrophage-differentiation and apoptosis was studied with 1A9-M cells expressing human BCL2 or a dominant-negative form of Stat3, respectively. IL-6–induced apoptosis, but not macrophage-differentiation, was blocked by continuously expressed BCL2. A dominant-negative form of Stat3 inhibited both macrophage-differentiation and apoptosis induced by IL-6. However, diminished Stat3 activity did not prevent IL-6–induced downregulation of the BCL2 gene. Therefore, activation of Stat3 is essential for IL-6–induced macrophage-differentiation and programmed cell death in this model. Whereas overexpression of BCL2 abrogates the apoptotic response, Stat3-independent signals appear to downregulate expression of the BCL2 gene.

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Interleukin‐5 deletion promotes sepsis‐induced M1 macrophage differentiation, deteriorates cardiac dysfunction, and exacerbates cardiac injury via the NF‐κB p65 pathway in mice

BioFactors ◽

10.1002/biof.1681 ◽

2020 ◽

Vol 46 (6) ◽

pp. 1006-1017

Author(s):

Wanqian Liang ◽

Jianhua Li ◽

Caiyan Bai ◽

Yingen Chen ◽

Yan Li ◽

...

Keyword(s):

Cardiac Dysfunction ◽

Cardiac Injury ◽

Macrophage Differentiation ◽

Interleukin 5 ◽

M1 Macrophage

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Retinoic acid inhibits interleukin-6-induced macrophage differentiation and apoptosis in a murine hematopoietic cell line, Y6

Blood ◽

10.1182/blood.v80.9.2298.2298 ◽

1992 ◽

Vol 80 (9) ◽

pp. 2298-2305 ◽

Cited By ~ 35

Author(s):

K Oritani ◽

T Kaisho ◽

K Nakajima ◽

T Hirano

Keyword(s):

Signal Transduction ◽

Retinoic Acid ◽

Cell Line ◽

Interleukin 6 ◽

Signal Transduction Pathway ◽

Inhibitory Effect ◽

Hematopoietic Cell ◽

Transduction Pathway ◽

Macrophage Differentiation ◽

Hematopoietic Cell Line

Abstract We established a radiation-induced murine hematopoietic cell line, Y6, that could be induced to differentiate into macrophages by interleukin- 6 (IL-6). IL-6 also induced growth inhibition and apoptosis in Y6 cells. Retinoic acid (RA) inhibited such effects of IL-6 on Y6 cells. The inhibitory effect of RA on the effects of IL-6 was not caused by the downregulation of the IL-6 receptor, because RA neither affected the expression of IL-6 receptor mRNA nor the expression of IL-6 receptor molecule on the cell surface. Furthermore, RA did not inhibit the IL-6-induced expression of junB mRNA, indicating that the expression of functionally active IL-6 receptor and the signal transduction pathway activating the junB gene are not inhibited by RA. IL-6-induced macrophage differentiation of Y6 cells was preceded by the downregulation of the c-myc gene, which was also prevented by RA. Because the inhibitory effect of RA on Y6 cells was reversible and seemed not to require de novo protein synthesis, the RA receptor by itself might be directly involved in the inhibition of the IL-6 signal transduction pathway. The results indicated that the IL-6 signal transduction pathways leading to the induction of macrophage differentiation and junB gene expression can be dissected by RA.

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Differential regulation of macrophage differentiation in response to leukemia inhibitory factor/oncostatin-M/interleukin-6: the effect of enforced expression of the SCL transcription factor

Blood ◽

10.1182/blood.v85.2.379.bloodjournal852379 ◽

1995 ◽

Vol 85 (2) ◽

pp. 379-390 ◽

Cited By ~ 3

Author(s):

T Tanigawa ◽

N Nicola ◽

GA McArthur ◽

A Strasser ◽

CG Begley

Keyword(s):

Growth Factors ◽

Interleukin 6 ◽

Leukemia Inhibitory Factor ◽

Differential Regulation ◽

Oncostatin M ◽

Inhibitory Factor ◽

Macrophage Phenotype ◽

Colony Stimulating Factor ◽

Macrophage Differentiation ◽

Stimulating Factor

The physiologic program of macrophage differentiation normally proceeds in a coordinated manner in response to several different growth factors. Although the utilization of common receptor subunits may explain in part overlapping biologic functions, mechanisms by which unique actions are mediated remain obscure. We examined growth factor- induced macrophage differentiation in M1 leukemia cells that simultaneously display receptors for interleukin-6 (IL-6), leukemia inhibitory factor (LIF) and Oncostatin-M (OSM). Differentiation induced by all three factors was associated with decreased expression of transcription factors myb and SCL, increased expression of macrophage markers, and suppression of proliferation. Cell lines were established in which SCL expression was enforced. In the absence of growth factors, cells were indistinguishable from parental cells. However, LIF (or OSM)- induced macrophage differentiation was perturbed; there was failure to undergo morphologic differentiation, disturbed expression of lysozyme and Mac1 alpha, and failure to suppress proliferation. Surprisingly the perturbation of macrophage differentiation did not apply to induced expression of macrophage colony-stimulating factor (M-CSF) or granulocyte colony stimulating factor (G-CSF) receptors. This dissociation of elements normally coordinated in a macrophage differentiation program applied at a clonal level. There was no disturbance of IL-6-induced macrophage differentiation. These data directly implicate SCL in components of the macrophage differentiation program (suggesting that LIF receptor/gp130 heterodimers utilize an SCL- inhibitable pathway while gp130 homodimers do not) and demonstrate differential-regulation of components of the mature macrophage phenotype.

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Differential regulation of macrophage differentiation in response to leukemia inhibitory factor/oncostatin-M/interleukin-6: the effect of enforced expression of the SCL transcription factor

Blood ◽

10.1182/blood.v85.2.379.379 ◽

1995 ◽

Vol 85 (2) ◽

pp. 379-390 ◽

Cited By ~ 37

Author(s):

T Tanigawa ◽

N Nicola ◽

GA McArthur ◽

A Strasser ◽

CG Begley

Keyword(s):

Growth Factors ◽

Interleukin 6 ◽

Leukemia Inhibitory Factor ◽

Differential Regulation ◽

Oncostatin M ◽

Inhibitory Factor ◽

Macrophage Phenotype ◽

Colony Stimulating Factor ◽

Macrophage Differentiation ◽

Stimulating Factor

Abstract The physiologic program of macrophage differentiation normally proceeds in a coordinated manner in response to several different growth factors. Although the utilization of common receptor subunits may explain in part overlapping biologic functions, mechanisms by which unique actions are mediated remain obscure. We examined growth factor- induced macrophage differentiation in M1 leukemia cells that simultaneously display receptors for interleukin-6 (IL-6), leukemia inhibitory factor (LIF) and Oncostatin-M (OSM). Differentiation induced by all three factors was associated with decreased expression of transcription factors myb and SCL, increased expression of macrophage markers, and suppression of proliferation. Cell lines were established in which SCL expression was enforced. In the absence of growth factors, cells were indistinguishable from parental cells. However, LIF (or OSM)- induced macrophage differentiation was perturbed; there was failure to undergo morphologic differentiation, disturbed expression of lysozyme and Mac1 alpha, and failure to suppress proliferation. Surprisingly the perturbation of macrophage differentiation did not apply to induced expression of macrophage colony-stimulating factor (M-CSF) or granulocyte colony stimulating factor (G-CSF) receptors. This dissociation of elements normally coordinated in a macrophage differentiation program applied at a clonal level. There was no disturbance of IL-6-induced macrophage differentiation. These data directly implicate SCL in components of the macrophage differentiation program (suggesting that LIF receptor/gp130 heterodimers utilize an SCL- inhibitable pathway while gp130 homodimers do not) and demonstrate differential-regulation of components of the mature macrophage phenotype.

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Doxorubicin cardiomyopathy-induced inflammation and apoptosis are attenuated by gene deletion of the kinin B1 receptor

Biological Chemistry ◽

10.1515/bc.2008.070 ◽

2008 ◽

Vol 389 (6) ◽

Cited By ~ 13

Author(s):

Dirk Westermann ◽

Olga Lettau ◽

Meike Sobirey ◽

Alexander Riad ◽

Michael Bader ◽

...

Keyword(s):

Interleukin 6 ◽

Cardiac Dysfunction ◽

Cardiac Tissue ◽

Mrna Levels ◽

Western Blots ◽

Cardiac Inflammation ◽

Akt Activation ◽

B1 Receptor ◽

Kinin B1 Receptor

Abstract Clinical use of the anthracycline doxorubicin (DOX) is limited by its cardiotoxic effects, which are attributed to the induction of apoptosis. To elucidate the possible role of the kinin B1 receptor (B1R) during the development of DOX cardiomyopathy, we studied B1R knockout mice (B1R-/-) by investigating cardiac inflammation and apoptosis after induction of DOX-induced cardiomyopathy. DOX control mice showed cardiac dysfunction measured by pressure-volume loops in vivo. This was associated with a reduced activation state of AKT, as well as an increased bax/bcl2 ratio in Western blots, indicating cardiac apoptosis. Furthermore, mRNA levels of the proinflammatory cytokine interleukin 6 were increased in the cardiac tissue. In DOX B1R-/- mice, cardiac dysfunction was improved compared to DOX control mice, which was associated with normalization of the bax/bcl-2 ratio and interleukin 6, as well as AKT activation state. These findings suggest that B1R is detrimental in DOX cardiomyopathy in that it mediates the inflammatory response and apoptosis. These insights might have useful implications for future studies utilizing B1R antagonists for treatment of human DOX cardiomyopathy.

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Interleukin-6 expression and its modulation by diacerein in a rat model of chronic stress induced cardiac dysfunction

Heliyon ◽

10.1016/j.heliyon.2021.e08522 ◽

2021 ◽

pp. e08522

Author(s):

Vipul Agarwal ◽

Arjun Singh Kaushik ◽

Mujeeba Rehman ◽

Rishabh Chaudhary ◽

Talha Jawaid ◽

...

Keyword(s):

Chronic Stress ◽

Rat Model ◽

Interleukin 6 ◽

Cardiac Dysfunction

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Retinoic acid inhibits interleukin-6-induced macrophage differentiation and apoptosis in a murine hematopoietic cell line, Y6

Blood ◽

10.1182/blood.v80.9.2298.bloodjournal8092298 ◽

1992 ◽

Vol 80 (9) ◽

pp. 2298-2305 ◽

Cited By ~ 1

Author(s):

K Oritani ◽

T Kaisho ◽

K Nakajima ◽

T Hirano

Keyword(s):

Signal Transduction ◽

Retinoic Acid ◽

Cell Line ◽

Interleukin 6 ◽

Signal Transduction Pathway ◽

Inhibitory Effect ◽

Hematopoietic Cell ◽

Transduction Pathway ◽

Macrophage Differentiation ◽

Hematopoietic Cell Line

We established a radiation-induced murine hematopoietic cell line, Y6, that could be induced to differentiate into macrophages by interleukin- 6 (IL-6). IL-6 also induced growth inhibition and apoptosis in Y6 cells. Retinoic acid (RA) inhibited such effects of IL-6 on Y6 cells. The inhibitory effect of RA on the effects of IL-6 was not caused by the downregulation of the IL-6 receptor, because RA neither affected the expression of IL-6 receptor mRNA nor the expression of IL-6 receptor molecule on the cell surface. Furthermore, RA did not inhibit the IL-6-induced expression of junB mRNA, indicating that the expression of functionally active IL-6 receptor and the signal transduction pathway activating the junB gene are not inhibited by RA. IL-6-induced macrophage differentiation of Y6 cells was preceded by the downregulation of the c-myc gene, which was also prevented by RA. Because the inhibitory effect of RA on Y6 cells was reversible and seemed not to require de novo protein synthesis, the RA receptor by itself might be directly involved in the inhibition of the IL-6 signal transduction pathway. The results indicated that the IL-6 signal transduction pathways leading to the induction of macrophage differentiation and junB gene expression can be dissected by RA.

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Skewed Cytokine Responses Rather Than the Magnitude of the Cytokine Storm May Drive Cardiac Dysfunction in Multisystem Inflammatory Syndrome in Children

Journal of the American Heart Association ◽

10.1161/jaha.121.021428 ◽

2021 ◽

Author(s):

Joyce C. Chang ◽

Daisuke Matsubara ◽

Ryan W. Morgan ◽

Caroline Diorio ◽

Sumekala Nadaraj ◽

...

Keyword(s):

Interleukin 6 ◽

Cardiac Dysfunction ◽

Longitudinal Strain ◽

Acute Stress ◽

Global Longitudinal Strain ◽

Left Ventricular ◽

Stress Cardiomyopathy ◽

Interleukin 8 ◽

Right Ventricular Free Wall ◽

Inflammatory Syndrome

Background Cardiac dysfunction is a prominent feature of multisystem inflammatory syndrome in children (MIS‐C), yet the etiology is poorly understood. We determined whether dysfunction is global or regional, and whether it is associated with the cytokine milieu, microangiopathy, or severity of shock. Methods and Results We analyzed echocardiographic parameters of myocardial deformation and compared global and segmental left ventricular strain between 43 cases with MIS‐C ≤18 years old and 40 controls. Primary outcomes included left ventricular global longitudinal strain, right ventricular free wall strain), and left atrial strain. We evaluated relationships between strain and profiles of 10 proinflammatory cytokines, microangiopathic features (soluble C5b9), and vasoactive‐inotropic requirements. Compared with controls, cases with MIS‐C had significant impairments in all parameters of systolic and diastolic function. 65% of cases with MIS‐C had abnormal left ventricular function ( | global longitudinal strain | <17%), although elevations of cytokines were modest. All left ventricular segments were involved, without apical or basal dominance to suggest acute stress cardiomyopathy. Worse global longitudinal strain correlated with higher ratios of interleukin‐6 (ρ −0.43) and interleukin‐8 (ρ −0.43) to total hypercytokinemia, but not absolute levels of interleukin‐6 or interleukin‐8, or total hypercytokinemia. Similarly, worse right ventricular free wall strain correlated with higher relative interleukin‐8 expression (ρ −0.59). There were no significant associations between function and microangiopathy or vasoactive‐inotropic requirements. Conclusions Myocardial function is globally decreased in MIS‐C and not explained by acute stress cardiomyopathy. Cardiac dysfunction may be driven by the relative skew of the immune response toward interleukin‐6 and interleukin‐8 pathways, more so than degree of hyperinflammation, refining the current paradigm of myocardial involvement in MIS‐C.

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