There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.
Abstract
Tumour necrosis factor-alpha (TNF alpha) 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. TNF alpha acts as a negative regulator of haematopoiesis.
Here we investigated whether HLA-DR-mediated inhibition of haematopoiesis involved
TNF alpha and TNF alpha-dependent secondary signals. Anti-HLA-DR MAb H81.9 up-regulated
TNF alpha, as well as transforming growth factor beta, interleukin (IL)-1beta and
IL-6 in human marrow cells at the ribonucleic acid (RNA) and protein level. The effect
on TNF alpha 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 TNF alpha 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-TNF alpha 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 NFkappaB, which is involved in the transcription of TNF alpha.
NFkappaB 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.