Critical Conditions for Studying Interleukin‐11 Signaling In Vitro and Avoiding Experimental Artefacts

2021 ◽  
Vol 1 (9) ◽  
Author(s):  
Sivakumar Viswanathan ◽  
Benjamin Ng ◽  
Anissa A. Widjaja ◽  
Chee Jian Pua ◽  
Nevin Tham ◽  
...  
Keyword(s):  
Critical Conditions ◽  
Interleukin 11

The role of aromatic microbial metabolites

2018 ◽  
pp. 97-108
Author(s):  
Н.В. Белобородова ◽  
В.В. Мороз ◽  
А.Ю. Бедова
Keyword(s):  
Process Integration ◽  
Biological Effects ◽  
Clinical Findings ◽  
Multiple Organ ◽  
Critical Conditions ◽  
Clear Understanding ◽  
Microbial Metabolites ◽  
Blood Concentrations

Интеграция метаболизма макроорганизма и его микробиоты, обеспечивающая в норме симбиоз и саногенез, нарушается при заболеваниях, травме, критическом состоянии, и вектор взаимодействия может изменяться в пользу прокариотов по принципу «метаболиты бактерий - против хозяина». Анализ литературы показал, что, с одной стороны, имеется живой интерес к ароматическим микробным метаболитам, с другой - отсутствует четкое представление об их роли в организме человека. Публикации, касающиеся ряда ароматических микробных метаболитов (фенилкарбоновых кислот, ФКК), как правило, не связаны между собой по тематике и направлены на решение тех или иных прикладных задач в разных областях биологии и медицины. Цель обзора - анализ информации о происхождении, биологических эффектах ФКК в экспериментах in vitro и in vivo , и клинических наблюдениях. Обобщая результаты приведенных в обзоре исследований на клеточном, субклеточном и молекулярном уровнях, логично предположить участие ароматических микробных метаболитов в патогенезе полиорганной недостаточности при сепсисе. Наиболее перспективным для раскрытия роли ароматических микробных метаболитов представляется изучение механизмов вторичной почечной недостаточности и септической энцефалопатии. Важным направлением для будущих исследований является изучение влияния продуктов микробной биодеградации ароматических соединений на развитие диссеминированного внутрисосудистого свертывания крови, артериальной гипотензии и септического шока. Результаты дальнейших исследований будут иметь не только фундаментальное значение, но и обогатят практическую медицину новыми диагностическими и лечебными технологиями. Significant increases in blood concentrations of some aromatic metabolites (phenylcarboxylic acids, PhCAs) in patients with sepsis have been previously shown. Enhanced bacterial biodegradation of aromatic compounds has been demonstrated to considerably contribute to this process. Integration of macroorganism metabolism and its microbiota, which provides normal symbiosis and sanogenesis, is disturbed in diseases, trauma, and critical conditions. Direction of this interaction may change in favor of prokaryotes according to the principle, “bacterial metabolites are against the host”. Analysis of literature showed a particular interest of many investigators to aromatic microbial metabolites. However, there is no clear understanding of their role in the human body. Publications on PhCAs are generally not thematically interrelated and usually focus on solving applied tasks in different fields of biology and medicine. The aim of this work was to consolidate existing information about origin and biological effects of PhCAs in in vitro / in vivo experiments and some clinical findings. The presented summary of reported data from studies performed at cellular, sub-cellular, and molecular levels suggests participation of aromatic microbial metabolites in the pathogenesis of multiple organ failure in sepsis. Studying mechanisms of secondary renal failure and septic encephalopathy is most promising for discovering the function of aromatic microbial metabolites. Effects of microbial biodegradation products of aromatic substances on development of disseminated intravascular coagulation, hypotension, and septic shock are an important challenge for future studies. Results of further investigations will be not only fundamental, but will also enrich medical practice with new diagnostic and therapeutic technologies.

scholarly journals Interleukin-11 inhibits adipogenesis and stimulates myelopoiesis in human long-term marrow cultures

Blood ◽  
1993 ◽  
Vol 82 (5) ◽  
pp. 1428-1435 ◽  
Author(s):  
DC Keller ◽  
XX Du ◽  
EF Srour ◽  
R Hoffman ◽  
DA Williams
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Lymphoid Cells ◽  
Adherent Cell ◽  
Erythroid Progenitor ◽  
Hla Dr ◽  
Interleukin 11 ◽  
Marrow Cultures

Abstract Interleukin-11 (IL-11) is a bone marrow (BM) stromal-derived growth factor that has been shown to stimulate murine myeloid and lymphoid cells both in vitro and in vivo and to inhibit adipogenesis in a murine fibroblast cell line. We have studied the effects of IL-11 on highly purified human BM stem and progenitor cells and on human long-term marrow cultures (LTMC). Adipocyte differentiation is an integral component of murine and human LTMC. IL-11 stimulates myeloid growth as a single cytokine when added to highly enriched CD34+, HLA-DR+ bone marrow cells. IL-11 stimulated no growth in the more primitive CD34+, HLA-DR- population even in the presence of additional cytokines. IL-11 addition to human LTMC resulted in the expansion of myeloid and mixed, but not erythroid, progenitor populations. IL-11 dramatically increased the adherent cell populations, including both stromal cells and macrophages. Treated cultures also showed marked inhibition of fat accumulation in the adherent cells due in part to a block in the differentiation of preadipocytes to adipocytes, as shown by RNA analysis using adipocyte-specific markers. These data show that IL-11 stimulates a more differentiated, although multipotential, progenitor cell in human BM and that LTMC provide a useful model for studying the effects of this cytokine in the context of the hematopoietic microenvironment.

scholarly journals Interleukin-11 acts as an autocrine growth factor for human megakaryoblastic cell lines

Blood ◽  
1993 ◽  
Vol 81 (4) ◽  
pp. 889-893 ◽  
Author(s):  
S Kobayashi ◽  
M Teramura ◽  
I Sugawara ◽  
K Oshimi ◽  
H Mizoguchi
Keyword(s):  
Growth Factor ◽  
Cell Lines ◽  
Antisense Oligonucleotides ◽  
Leukemia Cell ◽  
Dependent Manner ◽  
Autocrine Growth ◽  
Autocrine Loop ◽  
Autocrine Growth Factor ◽  
Interleukin 11

Abstract The cytokine interleukin-11 (IL-11) promotes normal human megakaryocytopoiesis in vitro. However, its role in abnormal megakaryocytopoiesis is not well known. Accordingly, we studied its effects on human megakaryoblastic cell lines CMK and Meg-J. IL-11 stimulated the proliferation of CMK and Meg-J in a dose-dependent manner with maximal growth being achieved at the concentration of 50 and 500 ng/mL, respectively. The growth of the cells was inhibited by anti-IL-11 antibody and IL-11 antisense oligonucleotides. IL-11 transcripts were detected in these two cell lines using a reverse transcriptase-polymerase chain reaction assay. These findings indicate that IL-11 might be an autocrine growth factor for megakaryoblastic cells. IL-11 transcripts also existed in other leukemia cell lines: HL- 60, U937, and K562. However, the growth of these cells was not stimulated by IL-11, and was not inhibited by IL-11 antisense oligonucleotides. These results suggested that IL-11 might regulate malignant cells of the megakaryocytic lineage, in part by an autocrine loop.

scholarly journals Enhancement of in vitro and in vivo antigen-specific antibody responses by interleukin 11.

1992 ◽  
Vol 175 (1) ◽  
pp. 211-216 ◽  
Author(s):  
T G Yin ◽  
P Schendel ◽  
Y C Yang
Keyword(s):  
T Cells ◽  
Antibody Titer ◽  
Specific Antibody ◽  
Antibody Responses ◽  
Rabbit Serum ◽  
Dependent Manner ◽  
Dose Dependent ◽  
Interleukin 11

The availability of large quantities of highly purified recombinant interleukin 11 (rhuIL-11) has allowed us to investigate the effects of rhuIL-11 on sheep red blood cell (SRBC)-specific antibody responses in the murine system. The results showed that rhuIL-11 was effective in enhancing the generation of mouse spleen SRBC-specific plaque-forming cells (PFC) in the in vitro cell culture system in a dose-dependent manner. These effects of rhuIL-11 were abrogated completely by the addition of anti-rhuIL-11 antibody, but not by the addition of preimmunized rabbit serum. Cell-depletion studies revealed that L3T4 (CD4)+ T cells, but not Lyt-2 (CD8)+ T cells, are required in the rhuIL-11-stimulated augmentation of SRBC-specific antibody responses. The effects of rhuIL-11 on the SRBC-specific antibody responses in vivo were also examined. RhuIL-11 administration to normal C3H/HeJ mice resulted in a dose-dependent increase in the number of spleen SRBC-specific PFC as well as serum SRBC-specific antibody titer in both the primary and secondary immune responses. In mice immunosuppressed by cyclophosphamide treatment, rhuIL-11 administration significantly augmented the number of spleen SRBC-specific PFC as well as serum SRBC-specific antibody titer when compared with the cyclophosphamide-treated mice without IL-11 treatment. These results demonstrated that IL-11 is a novel cytokine involved in modulating antigen-specific antibody responses in vitro as well as in vivo.

Improvement of pharmacokinetic, pharmacodynamic and thrombopoietic activities of human interleukin-11 mutein by PEGylation.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e19574-e19574
Author(s):  
Seong-Hyun Ho ◽  
Seung Shin Yu ◽  
Jong-Mook Kim ◽  
Sunyoung Kim ◽  
Suyong Ma ◽  
...  
Keyword(s):  
Biological Activities ◽  
Fold Increase ◽  
Control Group ◽  
High Dose ◽  
Platelet Recovery ◽  
Clinical Dose ◽  
Equivalent Efficacy ◽  
Mean Time ◽  
Interleukin 11

e19574 Background: Chemical modification of recombinant human interleukin-11 (rhIL-11) by polyethylene glycol improved the pharmacokinetics (PK), but not remaining biological activity. Human interleukin-11 mutein (mIL-11) has been shown the improved safety and equivalent efficacy at one-third of the clinical dose of rhIL-11 in chemotherapy-induced thrombocytopenia (CIT) patients. Methods: To evaluate whether PEGylated mIL-11 (PEG-mIL-11) could reduce the toxicity and the frequency of administration without compromising biological activities, comparative preclinical studies on PEG-mIL-11 and mIL-11 in normal and myelosuppressed animals were performed. Results: In vitro biological assay showed that the ED50 value of purified mono-PEG-mIL11 was comparable to that of mIL-11. The PK parameters such as AUC of PEG-mIL-11 were at least 4-fold larger than those of mIL-11 at the same dosage. The thrombopoietic activity resulting from a single PEG-mIL-11 administration was almost similar to that achieved from multiple administrations of mIL-11 in normal rodents and monkeys. In myelosuppressed model, PEG-mIL-11 was s.c. administered twice at doses of 200, 420 or 900 μg/kg and the platelet number of each group was compared with that of control group injected with 200 μg/kg of mIL-11 once daily for 9 days. The high dose group of PEG-mIL-11 showed 2-fold increase in the nadir platelet count and the mean time to platelet recovery of PEG-mIL-11 groups was shortened up to a maximum of 7 days as compared with mIL-11 or untreated group. PEG-mIL-11 also significantly prevented the reduction of WBC and RBC counts which was considered a major hematological AE of chemotherapy and radiotherapy for cancer as compared with mIL-11 or naïve group. Conclusions: These results suggest that the PEG-mIL-11 show improved PK profile without compromising biological activities and prevent CIT more effectively with better safety profile than mIL-11.

scholarly journals Effect of interleukin-11 on cycling status and clonogenic maturation of fetal and adult hematopoietic progenitors

Blood ◽  
1992 ◽  
Vol 80 (4) ◽  
pp. 900-903
Author(s):  
KR Schibler ◽  
YC Yang ◽  
RD Christensen
Keyword(s):  
Cell Cycle ◽  
Tritiated Thymidine ◽  
Single Agent ◽  
Hematopoietic Progenitors ◽  
Gm Csf ◽  
Colony Forming Units ◽  
Cell Cycle Status ◽  
Interleukin 11 ◽  
Human Cytokine

A recently cloned human cytokine, interleukin-11 (IL-11), has functional similarities to IL-6. We tested the hypothesis that the hematopoietic actions of IL-11 in vitro also resemble those of IL-6. The effect of IL-11 on the cell cycle status of fetal and adult hematopoietic progenitors was assessed using serum-free incubations followed by tritiated thymidine suicide studies. Its effect on clonogenic maturation was assessed by including IL-11, either as a single agent or with subplateau or plateau concentrations of other recombinant cytokines, in cultures that contained neutralizing monoclonal antibodies directed against relevant growth factors. Similar to IL-6, IL-11 resulted in accelerated cycling of fetal colony-forming units-mixed (CFU-MIX), CFU-granulocyte macrophage (CFU-GM), and erythroid burst-forming units (BFU-E). This effect was additive to that of submaximal, but not to plateau, concentrations of IL-6. However, no effect of IL-11 was observed on cycling status of adult progenitors. As a single agent, IL-11 failed to support clonal maturation of either fetal or adult progenitors. IL-11 was additive to GM-CSF in supporting clonal maturation of CFU-GM from adult marrow but not from fetal blood. We conclude that the in vitro hematopoietic actions of IL-11 on cell cycle status of hematopoietic progenitors resemble those of IL-6. However, unlike IL-6, IL-11 as a single agent failed to support clonal maturation of fetal CFU-GM, BFU-E, and CFU-MIX.

In vitro studies of stem cell factor (SCF) and interleukin-11 (IL-11) in normal and “preleukemic” haematopoiesis

1993 ◽  
Vol 29 ◽  
pp. S52
Author(s):  
T. Bammer ◽  
P. Fenaux ◽  
S. Gaggl ◽  
D. Geissler ◽  
H. Zwierzina
Keyword(s):  
Stem Cell ◽  
Stem Cell Factor ◽  
In Vitro Studies ◽  
Interleukin 11

scholarly journals Interleukin-11 stimulates multiple phases of erythropoiesis in vitro

Blood ◽  
1992 ◽  
Vol 80 (5) ◽  
pp. 1218-1223
Author(s):  
VF Quesniaux ◽  
SC Clark ◽  
K Turner ◽  
B Fagg
Keyword(s):  
Bone Marrow ◽  
Erythroid Differentiation ◽  
Erythroid Progenitors ◽  
Murine Bone Marrow ◽  
Kit Ligand ◽  
B Cell Maturation ◽  
Stromal Cell Line ◽  
Interleukin 11

Interleukin-11 (IL-11), a pleiotropic cytokine originally isolated from a primate bone marrow stromal cell line, has been shown to stimulate T- cell-dependent B-cell maturation, megakaryopoiesis, and various stages of myeloid differentiation, but to inhibit adipogenesis. Because stromal cells are essential for the maintenance of early hematopoietic progenitor cells in long-term culture, we investigated the effects of IL-11 on multipotent and erythroid precursors from murine bone marrow in vitro in suspension and semisolid cultures. Our results show that in the presence of IL-3 or c-kit ligand (KL), IL-11 has profound stimulatory effects on primitive multilineage hematopoietic progenitors, pre-CFC(multi), as well as on precursors representing various stages of erythroid differentiation observable in vitro, including CFC(multi), BFU-E, and CFU-E. In addition, the combination of KL with IL-11 also stimulated highly proliferative erythroid progenitors that yield remarkable macroscopic erythroblast colonies in culture. These results indicate that IL-11 is likely to play a pivotal role in early hematopoiesis and at multiple stages of erythropoiesis.

scholarly journals Recombinant human interleukin-11 stimulates multilineage hematopoietic recovery in mice after a myelosuppressive regimen of sublethal irradiation and carboplatin

Blood ◽  
1994 ◽  
Vol 83 (6) ◽  
pp. 1499-1506 ◽  
Author(s):  
JP Leonard ◽  
CM Quinto ◽  
MK Kozitza ◽  
TY Neben ◽  
SJ Goldman
Keyword(s):  
Bone Marrow ◽  
Peripheral Circulation ◽  
Effective Agent ◽  
Hematopoietic Recovery ◽  
Study Support ◽  
Pleiotropic Properties ◽  
Interleukin 11 ◽  
Hematopoietic Activity ◽  
Sublethal Irradiation

Interleukin-11 (IL-11) is a novel multifunctional hematopoietic cytokine capable of stimulating cells of the myeloid, lymphoid, erythroid, and megakaryocytic lineages in vitro. We have tested the pleiotropic properties of this cytokine on the hematopoietic recovery of mice after a combined regimen of sublethal irradiation and carboplatin administration. This regimen results in severe myelosuppression, characterized by a prolonged period of thrombocytopenia and severe anemia. Administration of recombinant human IL-11 (rhIL-11; 250 micrograms/kg/d) had multilineage effects on bone marrow and spleen hematopoietic activity, increasing the number of megakaryocyte, erythroid, granulocyte, and macrophage progenitors compared with the vehicle-treated controls. This was reflected in the peripheral circulation by a reduction of both the platelet and hematocrit nadirs and a significantly reduced period of thrombocytopenia and anemia in the rhIL-11-treated mice. The results from this study support the broad spectrum of biologic activities that have been attributed to rhIL-11 in vitro and suggest that this cytokine may be an effective agent in the treatment of myelosuppression associated with cancer chemotherapy and bone marrow transplantation.

scholarly journals Interleukin-11 acts as an autocrine growth factor for human megakaryoblastic cell lines

Blood ◽  
1993 ◽  
Vol 81 (4) ◽  
pp. 889-893 ◽  
Author(s):  
S Kobayashi ◽  
M Teramura ◽  
I Sugawara ◽  
K Oshimi ◽  
H Mizoguchi
Keyword(s):  
Growth Factor ◽  
Cell Lines ◽  
Antisense Oligonucleotides ◽  
Leukemia Cell ◽  
Dependent Manner ◽  
Autocrine Growth ◽  
Autocrine Loop ◽  
Autocrine Growth Factor ◽  
Interleukin 11

The cytokine interleukin-11 (IL-11) promotes normal human megakaryocytopoiesis in vitro. However, its role in abnormal megakaryocytopoiesis is not well known. Accordingly, we studied its effects on human megakaryoblastic cell lines CMK and Meg-J. IL-11 stimulated the proliferation of CMK and Meg-J in a dose-dependent manner with maximal growth being achieved at the concentration of 50 and 500 ng/mL, respectively. The growth of the cells was inhibited by anti-IL-11 antibody and IL-11 antisense oligonucleotides. IL-11 transcripts were detected in these two cell lines using a reverse transcriptase-polymerase chain reaction assay. These findings indicate that IL-11 might be an autocrine growth factor for megakaryoblastic cells. IL-11 transcripts also existed in other leukemia cell lines: HL- 60, U937, and K562. However, the growth of these cells was not stimulated by IL-11, and was not inhibited by IL-11 antisense oligonucleotides. These results suggested that IL-11 might regulate malignant cells of the megakaryocytic lineage, in part by an autocrine loop.

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