scholarly journals Inhibition of interleukin 1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody.

1991 ◽  
Vol 173 (4) ◽  
pp. 931-939 ◽  
Author(s):  
K W McIntyre ◽  
G J Stepan ◽  
K D Kolinsky ◽  
W R Benjamin ◽  
J M Plocinski ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Receptor Antagonist ◽  
Intraperitoneal Injection ◽  
Inflammatory Responses ◽  
Interleukin 1 ◽  
Type I ◽  
Type Ii ◽  
Ic50 Values

Recombinant human interleukin 1 receptor antagonist (IL-1ra) and 35F5, a neutralizing monoclonal antibody (mAb) to the type I mouse IL-1 receptor, were examined for their ability to bind to IL-1 receptors (IL-1Rs) on various types of mouse cells and to block immune and inflammatory responses to IL-1 in vitro and in mice. IL-1ra competed for binding of 125I-IL-1 alpha to type I IL-1R present on EL-4 thymoma cells, 3T3 fibroblasts, hepatocytes, and Chinese hamster ovary cells expressing recombinant mouse type I IL-1R. The IC50 values for IL-1ra binding (ranging from 2 to 4 ng/ml) were similar to those of IL-1 alpha. In contrast, IL-1ra bound with very low affinity (IC50 values ranging from 10 to 200 micrograms/ml) to cells expressing type II IL-1R, i.e., 70Z/3 pre-B cell line and polymorphonuclear leukocytes (PMN) derived from bone marrow and acute inflammatory exudates. The mAb 35F5 bound specifically to type I IL-1R; no inhibition of 125I-IL-1 alpha binding to cells having type II IL-1R was observed with very high concentrations of antibody. While neither IL-1ra nor 35F5 had intrinsic activity in bioassays using T helper D10.G4.1 cells and mouse thymocytes, both agents blocked the ability of IL-1 to stimulate proliferation of these cells. The effects of IL-1ra and 35F5 on acute inflammatory responses in mice were also evaluated. IL-1ra and 35F5 blocked the local accumulation of PMN after intraperitoneal injection of rIL-1 alpha. The response to IL-1 was inhibited when IL-1ra or 35F5 was administered simultaneously with or before administration of IL-1. IL-1ra and 35F5 also blocked PMN accumulation after intraperitoneal injection of lipopolysaccharide or proteose peptone, suggesting IL-1 is important in mediating responses to these agents. In addition, IL-1ra and 35F5 significantly blocked the ability of IL-1 to stimulate egress of PMN from bone marrow, to induce a transient neutrophilia, and to elevate serum levels of hepatic acute phase proteins, IL-6, and corticosterone. Thus, IL-1ra and 35F5 competitively inhibit the binding of IL-1 to the IL-1R on certain cell types. These two IL-1 receptor antagonists act to inhibit biological responses induced by IL-1 and other inflammatory agents.

scholarly journals Hematopoietic growth factors upregulate the p65 type II interleukin-1 receptor on bone marrow progenitor cells in vitro

Blood ◽  
1992 ◽  
Vol 80 (3) ◽  
pp. 600-608 ◽  
Author(s):  
CM Dubois ◽  
FW Ruscetti ◽  
SE Jacobsen ◽  
JJ Oppenheim ◽  
JR Keller
Keyword(s):  
Bone Marrow ◽  
Growth Factors ◽  
Progenitor Cells ◽  
Specific Binding ◽  
Interleukin 1 ◽  
Scatchard Analysis ◽  
Type I ◽  
Type Ii ◽  
Hematopoietic Growth Factors

Abstract Having previously shown that interleukin-1 (IL-1) induces the expression of IL-1 receptors (IL-1Rs) on bone marrow (BM) cells in vivo through an indirect mechanism, we studied whether hematopoietic growth factors (HGFs) could induce the expression of IL-1R on BM cells in vitro. In vitro treatment of light-density murine BM (LDBM) cells with either IL-3, IL-6, granulocyte--colony-stimulating factor (CSF), or granulocyte-macrophage--CSF caused a 5- to 10-fold upregulation of IL- 1R expression, whereas IL-1, IL-5, IL-7, and macrophage-CSF had no effect. Scatchard analysis showed one class of IL-1Rs on LDBM cells with an average of 66 +/- 20 sites per cells. After 24 hours of treatment with IL-3, the number of IL-1Rs increased to 413 +/- 125, without effecting the affinity. This effect required protein synthesis, but was independent of cell division. Purified lineage-negative progenitor cells (Lin-) did not express detectable levels of IL-1R, but 24 hours of treatment with IL-3, GM-CSF, and G-CSF stimulated IL-1-- specific binding. Autoradiographic analysis of Lin- cells showed that IL-1R induction by IL-3 occurs on undifferentiated blast cells. Affinity labeling of Lin- cells treated with HGFs showed an increase in a 65-Kd IL-1 binding protein that did not bind or compete with an anti- type I IL-1R antibody, suggesting that these cells expressed type II IL- 1R. These data suggest that IL-1 stimulation of myelopoiesis occurs by a mechanism involving IL-1R upregulation on hematopoietic progenitor cells by HGFs.

scholarly journals Hematopoietic growth factors upregulate the p65 type II interleukin-1 receptor on bone marrow progenitor cells in vitro

Blood ◽  
1992 ◽  
Vol 80 (3) ◽  
pp. 600-608
Author(s):  
CM Dubois ◽  
FW Ruscetti ◽  
SE Jacobsen ◽  
JJ Oppenheim ◽  
JR Keller
Keyword(s):  
Bone Marrow ◽  
Growth Factors ◽  
Progenitor Cells ◽  
Specific Binding ◽  
Interleukin 1 ◽  
Scatchard Analysis ◽  
Type I ◽  
Type Ii ◽  
Hematopoietic Growth Factors

Having previously shown that interleukin-1 (IL-1) induces the expression of IL-1 receptors (IL-1Rs) on bone marrow (BM) cells in vivo through an indirect mechanism, we studied whether hematopoietic growth factors (HGFs) could induce the expression of IL-1R on BM cells in vitro. In vitro treatment of light-density murine BM (LDBM) cells with either IL-3, IL-6, granulocyte--colony-stimulating factor (CSF), or granulocyte-macrophage--CSF caused a 5- to 10-fold upregulation of IL- 1R expression, whereas IL-1, IL-5, IL-7, and macrophage-CSF had no effect. Scatchard analysis showed one class of IL-1Rs on LDBM cells with an average of 66 +/- 20 sites per cells. After 24 hours of treatment with IL-3, the number of IL-1Rs increased to 413 +/- 125, without effecting the affinity. This effect required protein synthesis, but was independent of cell division. Purified lineage-negative progenitor cells (Lin-) did not express detectable levels of IL-1R, but 24 hours of treatment with IL-3, GM-CSF, and G-CSF stimulated IL-1-- specific binding. Autoradiographic analysis of Lin- cells showed that IL-1R induction by IL-3 occurs on undifferentiated blast cells. Affinity labeling of Lin- cells treated with HGFs showed an increase in a 65-Kd IL-1 binding protein that did not bind or compete with an anti- type I IL-1R antibody, suggesting that these cells expressed type II IL- 1R. These data suggest that IL-1 stimulation of myelopoiesis occurs by a mechanism involving IL-1R upregulation on hematopoietic progenitor cells by HGFs.

Localisation of mRNA for interleukin-1 receptor and interleukin-1 receptor antagonist in the rat ovary

1997 ◽  
Vol 152 (1) ◽  
pp. 11-17 ◽  
Author(s):  
L-J Wang ◽  
M Brännström ◽  
K-H Cui ◽  
A P Simula ◽  
R P Hart ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Ovarian Function ◽  
Interleukin 1 ◽  
Target Cells ◽  
Corpora Lutea ◽  
Similar Distribution ◽  
Type I ◽  
Mrna Levels ◽  
Primordial Follicles

Abstract Interleukin-1 (IL-1) is a multifunctional cytokine with profound effects on ovarian function. The effects of IL-1 on ovarian steroidogenesis have been demonstrated in several species. IL-1 mRNA levels are increased in the thecal layer of the ovulating follicle and IL-1β has been shown to induce ovulations in vitro. In this study we have investigated the presence and distribution of the mRNAs for type I IL-1 receptor (IL-1RtI) and for the naturally occurring IL-1 receptor antagonist (IL-1ra) in ovaries of adult cycling rats, to elucidate the target cells for IL-1 action. We have demonstrated the presence of mRNA for both substances by in situ hybridisation and reverse transcription PCR. mRNA for IL-1RtI was not found in primordial follicles but was abundant in the granulosa and thecal layer in developing follicles with stronger signals in the granulosa layer. In the preovulatory and ovulatory follicles, there was a further increase in the signal for IL-1RtI mRNA in the thecal layer compared with the granulosa layer. Corpora lutea were weakly positive at all stages and atretic follicles were largely negative. No mRNA was detected in oocytes of any stage. mRNA for IL-1ra showed a similar distribution to that of IL-1RtI. The changes in distribution suggest an action of IL-1 on rat granulosa cells during follicular development and on thecal cells during ovulation. Journal of Endocrinology (1997) 152, 11–17

Importance of brain IL-1 type II receptors in fever and thermogenesis in the rat

1993 ◽  
Vol 265 (4) ◽  
pp. E585-E591 ◽  
Author(s):  
G. Luheshi ◽  
S. J. Hopkins ◽  
R. A. Lefeuvre ◽  
M. J. Dascombe ◽  
P. Ghiara ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Low Dose ◽  
Interleukin 1 ◽  
Type I ◽  
Intracerebroventricular Injection ◽  
Type Ii ◽  
Central Effects ◽  
Conscious Rats ◽  
Central Actions ◽  
The Brain

Interleukin-1 (IL-1) acts centrally to induce fever and thermogenesis in rodents. The central actions of IL-1 alpha and IL-1 beta apparently involve different mechanisms, and the effects of IL-1 beta are not consistent with interaction with a type I (IL-1RI) 80-kDa receptor. In the present study the involvement of the type II IL-1 receptor (IL-1RII) was tested in the rat by examining the effects of central injection of a monoclonal antibody (ALVA-42), which blocks the IL-1RII. Pretreatment of rats with ALVA-42 (6 micrograms icv) inhibited the thermogenic and pyrogenic responses to intracerebroventricular injection of 5 ng (but not 50 ng) of IL-1 beta in conscious rats but did not significantly modify responses to IL-1 alpha. ALVA-42 also failed to modify the responses to peripherally administered IL-1 beta (1 microgram) but significantly attenuated the pyrogenic and thermogenic responses to peripheral (125 micrograms) or central (1 microgram) injection of endotoxin. These data indicate that IL-1RII mediates the central effects of a low dose of IL-1 beta, but not IL-1 alpha, on fever and thermogenesis in the rat. They also imply that responses to endotoxin are due, at least in part, to the activation of IL-1RII by IL-1 beta released within the brain and that effects of peripherally injected IL-1 beta involve different mechanisms, probably associated with IL-1RI.

scholarly journals In vivo interleukin-1 (IL-1) administration indirectly promotes type II IL-1 receptor expression on hematopoietic bone marrow cells: novel mechanism for the hematopoietic effects of IL-1

Blood ◽  
1991 ◽  
Vol 78 (11) ◽  
pp. 2841-2847 ◽  
Author(s):  
CM Dubois ◽  
FW Ruscetti ◽  
JR Keller ◽  
JJ Oppenheim ◽  
K Hestdal ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Direct Action ◽  
Interleukin 1 ◽  
Receptor Expression ◽  
Type I ◽  
Type Ii ◽  
Hematopoietic Growth Factors ◽  
Accessory Cells

Abstract Interleukin-1 (IL-1) has profound stimulatory effects on hematopoiesis but the mechanism(s) of action remain unknown. The direct action of IL- 1 on hematopoietic progenitor cells requires the presence of a specific IL-1 receptor (IL-1R). In this report, we tested the effect of in vivo IL-1 treatment on the expression of IL-1R on bone marrow (BM) cells. Injection of mice with IL-1 results in a marked upregulation of IL-1R on light-density BM cells as on a subpopulation enriched for myeloid precursors. Pretreatment of mice with anti-type I IL-1R antibody (35F5), which has been shown to prevent the radioprotective effect of IL-1, also blocked IL-1-induced IL-1R expression on BM cells. This antibody did not directly bind and block IL-1 binding to the type II IL- 1R expressed on hematopoietic cells, suggesting that IL-1R upregulation by IL-1 is indirect. It is therefore possible that IL-1 acts on type I IL-1R-expressing accessory cells such as stromal cells or T cells to induce production of hematopoietic growth factors (HGFs). In support of this, granulocyte colony-stimulating factor administration can induce the increase of IL-1R on BM cells. Thus, the increased expression of IL- 1R on hematopoietic BM cells by IL-1 is indirect, probably mediated in part through endogenous HGF production. These results also suggest that the restorative hematopoietic effect of IL-1 occurs through both indirect and direct mechanisms.

Congenital Amegakaryocytic Thrombocytopenia in a Thrombocytopenic Child Presenting without Amegakaryocytosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1110-1110
Author(s):  
Amy Geddis ◽  
Norma Fox ◽  
Hung Nguyen ◽  
Jennifer Keates-Baleeiro ◽  
Haydar Frangoul
Keyword(s):  
Bone Marrow ◽  
Stop Codon ◽  
Bone Marrow Failure ◽  
Type I ◽  
Severe Thrombocytopenia ◽  
Type Ii ◽  
Intracellular Domain ◽  
Platelet Antigen ◽  
Exon 11

Abstract Congenital amegakaryocytic thrombocytopenia (CAMT) is an inherited bone marrow syndrome due mutation of the thrombopoietin receptor c-Mpl. Affected children present with thrombocytopenia at birth and absence or severe reduction of megakaryocytes in the bone marrow and usually progress to complete bone marrow failure within the first decade of life. Mutations of c-Mpl have been classified as either type I mutations, in which the receptor has lost all activity, or type II mutations, in which the receptor retains some degree of function. Clinically, type II patients have a slightly delayed onset of bone marrow failure (mean age 48 months) compared to type I patients (22 months). Here we describe a girl with CAMT who had a clinical course similar to patients with type I mutations but without marked amegakaryocytosis at onset. The patient was born with intracranial hemorrhage due to severe thrombocytopenia (platelets 17K), which was initially thought to be due to alloimmune thrombocytopenia because of consistent platelet antigen typing studies and because the child responded to transfusion with her mother’s platelets and not to random donor platelets. However, thrombocytopenia persisted and she did not respond to immune directed therapies such as IVIG, prednisone or Rituximab, and after 14 months of age she began to develop neutropenia and anemia and by 24 months she had progressed to severe aplastic anemia. Bone marrow evaluation at 3 months showed trileage hematopoiesis with only mildly decreased megakaryocytes although they were noted to be small with hypolobulated nuclei. By 6 months of age, however, megakaryocytes appeared mildly decreased but were morphologically unremarkable and the marrow showed increased hematogones. At 24 months, marrow cellularity had decreased to 5% of normal with frank amegakaryocytosis. Sequencing of c-Mpl revealed two heterozygous mutations, one at Arg102Pro in the extracellular domain and the other one resulting in a stop codon at amino acid 541 in the intracellular domain. Arg102Pro is the most commonly occurring mutation reported in CAMT and is generally associated with type II disease. 541Stop is the first mutation reported in exon 11 and results in truncation of the receptor shortly after the box 1 homology domain. Previous in vitro studies involving the murine homolog of this mutation, which is missing all but the proximal 28 amino acids of the intracellular domain, demonstrated that it does not signal in response to thrombopoietin. This case illustrates the variation in clinical phenotype that can be seen in CAMT and the importance of gene sequencing for accurate diagnosis.

Human IL-1 receptor antagonist partially suppresses LPS fever but not plasma levels of IL-6 in Fischer rats

1992 ◽  
Vol 263 (3) ◽  
pp. R653-R655 ◽  
Author(s):  
B. K. Smith ◽  
M. J. Kluger
Keyword(s):  
Receptor Antagonist ◽  
Plasma Levels ◽  
Biological Effects ◽  
Interleukin 1 ◽  
Type I ◽  
Type Ii ◽  
Fischer 344 Rats ◽  
Fischer 344 ◽  
Fischer Rats

A human recombinant interleukin-1 receptor antagonist (IL-1ra) recognizes the two known IL-1 receptors and blocks the binding and many biological effects of both IL-1 alpha and IL-1 beta. The effectiveness of IL-1ra in modifying the fever and plasma IL-6 responses elicited by lipopolysaccharide (LPS) in vivo was tested in Fischer 344 rats. Animals that received IL-1ra 0.5 mg/kg intraperitoneally followed 10 min later by 10 micrograms/kg of LPS displayed significantly lower mean fever responses 2-4 h after injection than rats that received vehicle and LPS (0.48 +/- 0.13 vs. 0.95 +/- 0.16 degrees C, P = 0.016). Plasma levels of IL-6 at 4 h after injection were not different in IL-1ra-treated rats compared with controls (407,725 vs. 729,169 U/ml). Based on our previous finding that preadministration of antiserum to IL-1 beta markedly suppressed plasma IL-6 after LPS, and recent evidence that molar excesses of IL-1ra blocked IL-1-induced circulating IL-6 levels, the possibility that IL-1 is responsible for the induction of bioactive IL-6 during inflammation cannot be ruled out. Similarly, the inability of the IL-1ra to completely suppress the febrile responses of rats to LPS in the present study may be dose related. Alternatively, the induction of bioactive IL-6 by IL-1 in the rat may be mediated primarily through some receptor other than the type I (e.g., the type II receptor).

scholarly journals Interleukin-1 (IL-1) directly and indirectly promotes hematopoietic cell growth through type I IL-1 receptor

Blood ◽  
1994 ◽  
Vol 84 (1) ◽  
pp. 125-132 ◽  
Author(s):  
K Hestdal ◽  
FW Ruscetti ◽  
R Chizzonite ◽  
M Ortiz ◽  
JM Gooya ◽  
...  
Keyword(s):  
Cell Growth ◽  
Synergistic Effect ◽  
Progenitor Cell ◽  
Synergistic Effects ◽  
Interleukin 1 ◽  
Type I ◽  
Type Ii ◽  
Hematopoietic Progenitor ◽  
Gm Csf

Abstract Interleukin-1 (IL-1) has been shown to stimulate hematopoietic progenitor cell growth both in vitro and in vivo. Although IL-1 alone lacks the ability to promote hematopoietic progenitor growth in vitro, it is a potent synergistic factor in combination with other colony- stimulating factors (CSFs). Because it was unknown whether type I (p80), type II (p68), or other IL-1-binding proteins mediated the synergistic effects of IL-1 on purified progenitor cells, we used the difference in immunoreactivity between type I and type II IL-1 receptor (IL-1R) to better assess the role of these receptors in hematopoietic progenitor growth. Therefore, the synergistic effects of IL-1 alpha on IL-3-, CSF-1-, and granulocyte macrophage (GM)-CSF-induced progenitor growth, both in CFU-c and single-cell assays, were determined in the presence of monoclonal antibodies (MoAbs) 35F5 and 4E2 that block the binding of IL-1 alpha to type I and type II IL-1R, respectively. The synergistic effect of IL-1 alpha on IL-3 responsive Lin- and Lin(-)-Thy- 1+ progenitors was indirectly mediated and could be inhibited by MoAb 35F5. In contrast, IL-1 alpha directly synergized with CSF-1 and GM-CSF to promote progenitor cell growth. The direct synergistic effect of IL- 1 alpha on CSF-1-induced progenitor growth was observed in all progenitor populations examined (Lin-, Lin-Thy-1+, and Lin-Thy-1-) and was inhibited by MoAb 35F5. However, the direct synergistic effect of IL-1 alpha on GM-CSF-responsive progenitors. Lin- and Lin-Thy-1+, was partially inhibited by MoAb 35F5. In contrast, the MoAb antitype II IL- 1R (MoAb 4E2) could not inhibit the direct synergistic effects of IL-1 alpha on CSF-1- or GM-CSF-induced progenitor growth. Thus, IL-1 alpha directly and indirectly stimulates the growth and differentiation of purified progenitors through the type I IL-1R but not the type II IL-1R.

Sign in / Sign up

Export Citation Format

Share Document