Induction of negative regulators of haematopoiesis in human bone marrow cells by HLA-DR cross-linking

Masaki Yamaguchi; Steve Nadler; Jong Wook Lee; H. Joachim Deeg

doi:10.1016/S0966-3274(99)80035-5

Induction of negative regulators of haematopoiesis in human bone marrow cells by HLA-DR cross-linking

Masaki Yamaguchi
, Steve Nadler
, Jong Wook Lee
, H. Joachim Deeg

Division of Hematology

Fred Hutchinson Cancer Research Center
Bristol-Myers Squibb
University of Washington

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

Tumour necrosis factor-alpha (TNFα) is up-regulated by cross-linking of major histocompatibility complex (MHC) class II [human leucocyte antigen (HLA)-DR] antigens on monocytes. This is done by a bacterial superantigen or anti-HLA-DR monoclonal antibody (MAb). We have previously shown that HLA-DR cross-linking results in inhibition of haematopoiesis and apoptosis. TNFα acts as a negative regulator of haematopoiesis. Here we investigated whether HLA-DR-mediated inhibition of haematopoiesis involved TNFα and TNFα-dependent secondary signals. Anti-HLA-DR MAb H81.9 up-regulated TNFα, as well as transforming growth factor β, interleukin (IL)-1β and IL-6 in human marrow cells at the ribonucleic acid (RNA) and protein level. The effect on TNFα was investigated further. Up-regulation was blocked by herbimycin A, consistent with a tyrosine kinase-dependent mechanism. Up-regulation was also blunted by the soluble TNF-receptor fusion protein TNFR:Fc, suggesting an autocrine amplification loop. Following TNFα up-regulation, there was increased expression of Fas (CD95) and Fas-ligand (Fas-L). Up-regulation of Fas and Fas-L was blocked by TNFR:Fc. Furthermore, MAb H81.9-induced apoptosis was prevented by anti-TNFα MAb and by the soluble Fas receptor, Fas-Ig, providing further evidence that the TNF effect was mediated via Fas. At the transcriptional level, cross-linking of HLA-DR by MAb H81.9 affects nuclear localization of NF(κ)B, which is involved in the transcription of TNFα. NF(κ)B activity is modified by changes in cellular redox potential, and we have shown that H81.9 affects redox potential as determined by the generation of nitric oxide. These data show that HLA-DR-initiated signals are able to trigger a cascade of negative regulators of haematopoiesis. This model provides an opportunity to dissect signalling pathways that may be involved in the development of spontaneous marrow failure, and to devise interventions aimed at protecting haematopoiesis.

Original language	English
Pages (from-to)	159-168
Number of pages	10
Journal	Transplant Immunology
Volume	7
Issue number	3
DOIs	https://doi.org/10.1016/S0966-3274(99)80035-5
State	Published - Sep 1999

Bibliographical note

Funding Information:
We thank CassandraB eckhama nd Vladimir Lesnikov, M.D., for carryingo ut the CFU-GM assays,D r Ralf Huss and Dr GeoffreyG ersukf or theirc riticalc ommentsa, nd Bonnie Larson and Helen Crawfordf or typingt he manuscriptW. e thankP eter Kiener, Ph.D., for providingF as-Iga nd A ‘Routt,P h.D., for providing TNFR:Fc. Supported by PHS grants CA18029, CA09515a nd HL36444a wardedb y the National Instituteso f Health, DHHS, Bethesda,M D. Masaki Yamaguchiw as the recipient of a fellowship from Kanazawa University, Kanazawa,J apan. Jong-Wook Lee was supportedb y a grant from Catholic University,S eoul,K orea. H Joachim Deegi s the recipiento f a grantf rom the Gabriella Rich Foundation

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10.1016/S0966-3274(99)80035-5

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@article{76c7a685e68a400b8ee32d05494e1dd3,

title = "Induction of negative regulators of haematopoiesis in human bone marrow cells by HLA-DR cross-linking",

abstract = "Tumour necrosis factor-alpha (TNFα) is up-regulated by cross-linking of major histocompatibility complex (MHC) class II [human leucocyte antigen (HLA)-DR] antigens on monocytes. This is done by a bacterial superantigen or anti-HLA-DR monoclonal antibody (MAb). We have previously shown that HLA-DR cross-linking results in inhibition of haematopoiesis and apoptosis. TNFα acts as a negative regulator of haematopoiesis. Here we investigated whether HLA-DR-mediated inhibition of haematopoiesis involved TNFα and TNFα-dependent secondary signals. Anti-HLA-DR MAb H81.9 up-regulated TNFα, as well as transforming growth factor β, interleukin (IL)-1β and IL-6 in human marrow cells at the ribonucleic acid (RNA) and protein level. The effect on TNFα was investigated further. Up-regulation was blocked by herbimycin A, consistent with a tyrosine kinase-dependent mechanism. Up-regulation was also blunted by the soluble TNF-receptor fusion protein TNFR:Fc, suggesting an autocrine amplification loop. Following TNFα up-regulation, there was increased expression of Fas (CD95) and Fas-ligand (Fas-L). Up-regulation of Fas and Fas-L was blocked by TNFR:Fc. Furthermore, MAb H81.9-induced apoptosis was prevented by anti-TNFα MAb and by the soluble Fas receptor, Fas-Ig, providing further evidence that the TNF effect was mediated via Fas. At the transcriptional level, cross-linking of HLA-DR by MAb H81.9 affects nuclear localization of NF(κ)B, which is involved in the transcription of TNFα. NF(κ)B activity is modified by changes in cellular redox potential, and we have shown that H81.9 affects redox potential as determined by the generation of nitric oxide. These data show that HLA-DR-initiated signals are able to trigger a cascade of negative regulators of haematopoiesis. This model provides an opportunity to dissect signalling pathways that may be involved in the development of spontaneous marrow failure, and to devise interventions aimed at protecting haematopoiesis.",

author = "Masaki Yamaguchi and Steve Nadler and Lee, \{Jong Wook\} and Deeg, \{H. Joachim\}",

note = "Funding Information: We thank CassandraB eckhama nd Vladimir Lesnikov, M.D., for carryingo ut the CFU-GM assays,D r Ralf Huss and Dr GeoffreyG ersukf or theirc riticalc ommentsa, nd Bonnie Larson and Helen Crawfordf or typingt he manuscriptW. e thankP eter Kiener, Ph.D., for providingF as-Iga nd A {\textquoteleft}Routt,P h.D., for providing TNFR:Fc. Supported by PHS grants CA18029, CA09515a nd HL36444a wardedb y the National Instituteso f Health, DHHS, Bethesda,M D. Masaki Yamaguchiw as the recipient of a fellowship from Kanazawa University, Kanazawa,J apan. Jong-Wook Lee was supportedb y a grant from Catholic University,S eoul,K orea. H Joachim Deegi s the recipiento f a grantf rom the Gabriella Rich Foundation",

year = "1999",

month = sep,

doi = "10.1016/S0966-3274(99)80035-5",

language = "English",

volume = "7",

pages = "159--168",

journal = "Transplant Immunology",

issn = "0966-3274",

publisher = "Elsevier B.V.",

number = "3",

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TY - JOUR

T1 - Induction of negative regulators of haematopoiesis in human bone marrow cells by HLA-DR cross-linking

AU - Yamaguchi, Masaki

AU - Nadler, Steve

AU - Lee, Jong Wook

AU - Deeg, H. Joachim

N1 - Funding Information: We thank CassandraB eckhama nd Vladimir Lesnikov, M.D., for carryingo ut the CFU-GM assays,D r Ralf Huss and Dr GeoffreyG ersukf or theirc riticalc ommentsa, nd Bonnie Larson and Helen Crawfordf or typingt he manuscriptW. e thankP eter Kiener, Ph.D., for providingF as-Iga nd A ‘Routt,P h.D., for providing TNFR:Fc. Supported by PHS grants CA18029, CA09515a nd HL36444a wardedb y the National Instituteso f Health, DHHS, Bethesda,M D. Masaki Yamaguchiw as the recipient of a fellowship from Kanazawa University, Kanazawa,J apan. Jong-Wook Lee was supportedb y a grant from Catholic University,S eoul,K orea. H Joachim Deegi s the recipiento f a grantf rom the Gabriella Rich Foundation

PY - 1999/9

Y1 - 1999/9

N2 - Tumour necrosis factor-alpha (TNFα) is up-regulated by cross-linking of major histocompatibility complex (MHC) class II [human leucocyte antigen (HLA)-DR] antigens on monocytes. This is done by a bacterial superantigen or anti-HLA-DR monoclonal antibody (MAb). We have previously shown that HLA-DR cross-linking results in inhibition of haematopoiesis and apoptosis. TNFα acts as a negative regulator of haematopoiesis. Here we investigated whether HLA-DR-mediated inhibition of haematopoiesis involved TNFα and TNFα-dependent secondary signals. Anti-HLA-DR MAb H81.9 up-regulated TNFα, as well as transforming growth factor β, interleukin (IL)-1β and IL-6 in human marrow cells at the ribonucleic acid (RNA) and protein level. The effect on TNFα was investigated further. Up-regulation was blocked by herbimycin A, consistent with a tyrosine kinase-dependent mechanism. Up-regulation was also blunted by the soluble TNF-receptor fusion protein TNFR:Fc, suggesting an autocrine amplification loop. Following TNFα up-regulation, there was increased expression of Fas (CD95) and Fas-ligand (Fas-L). Up-regulation of Fas and Fas-L was blocked by TNFR:Fc. Furthermore, MAb H81.9-induced apoptosis was prevented by anti-TNFα MAb and by the soluble Fas receptor, Fas-Ig, providing further evidence that the TNF effect was mediated via Fas. At the transcriptional level, cross-linking of HLA-DR by MAb H81.9 affects nuclear localization of NF(κ)B, which is involved in the transcription of TNFα. NF(κ)B activity is modified by changes in cellular redox potential, and we have shown that H81.9 affects redox potential as determined by the generation of nitric oxide. These data show that HLA-DR-initiated signals are able to trigger a cascade of negative regulators of haematopoiesis. This model provides an opportunity to dissect signalling pathways that may be involved in the development of spontaneous marrow failure, and to devise interventions aimed at protecting haematopoiesis.

AB - Tumour necrosis factor-alpha (TNFα) is up-regulated by cross-linking of major histocompatibility complex (MHC) class II [human leucocyte antigen (HLA)-DR] antigens on monocytes. This is done by a bacterial superantigen or anti-HLA-DR monoclonal antibody (MAb). We have previously shown that HLA-DR cross-linking results in inhibition of haematopoiesis and apoptosis. TNFα acts as a negative regulator of haematopoiesis. Here we investigated whether HLA-DR-mediated inhibition of haematopoiesis involved TNFα and TNFα-dependent secondary signals. Anti-HLA-DR MAb H81.9 up-regulated TNFα, as well as transforming growth factor β, interleukin (IL)-1β and IL-6 in human marrow cells at the ribonucleic acid (RNA) and protein level. The effect on TNFα was investigated further. Up-regulation was blocked by herbimycin A, consistent with a tyrosine kinase-dependent mechanism. Up-regulation was also blunted by the soluble TNF-receptor fusion protein TNFR:Fc, suggesting an autocrine amplification loop. Following TNFα up-regulation, there was increased expression of Fas (CD95) and Fas-ligand (Fas-L). Up-regulation of Fas and Fas-L was blocked by TNFR:Fc. Furthermore, MAb H81.9-induced apoptosis was prevented by anti-TNFα MAb and by the soluble Fas receptor, Fas-Ig, providing further evidence that the TNF effect was mediated via Fas. At the transcriptional level, cross-linking of HLA-DR by MAb H81.9 affects nuclear localization of NF(κ)B, which is involved in the transcription of TNFα. NF(κ)B activity is modified by changes in cellular redox potential, and we have shown that H81.9 affects redox potential as determined by the generation of nitric oxide. These data show that HLA-DR-initiated signals are able to trigger a cascade of negative regulators of haematopoiesis. This model provides an opportunity to dissect signalling pathways that may be involved in the development of spontaneous marrow failure, and to devise interventions aimed at protecting haematopoiesis.

UR - https://www.scopus.com/pages/publications/0032694521

U2 - 10.1016/S0966-3274(99)80035-5

DO - 10.1016/S0966-3274(99)80035-5

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SN - 0966-3274

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JO - Transplant Immunology

JF - Transplant Immunology

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ER -

Induction of negative regulators of haematopoiesis in human bone marrow cells by HLA-DR cross-linking

Abstract

Bibliographical note

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