A mechanistic investigation of imflammatory murine monocytopoiesis

Author

Melinda S. Detrick

Date of Award

5-1994

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Major

Microbiology

Major Professor

Robert N. Moore

Committee Members

Tom Montie, Phil Bochsler, Barry Rouse

Abstract

During inflammation stimulated host effector and accessory cells release a variety of biological response modifiers (BRMs) that control the immune response. The release of agents such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF_alpha:), and nitrogen monoxide (NO) are important not only in protecting the host from invading foreign organisms, but also in pathological conditions resulting from their overproduction. The data generated in this study define another function of these proinflammatory molecules. Using information derived from a murine bone marrow culture system and assays detecting the production of NO, guanosine 3':5' cyclic monophosphate (cGMP), and specific mRNA transcripts, two pathways responsible for augmented production of monocytes and macrophages from bone marrow precommitment progenitors are defined. The pathways are incompatible with each other but individually control a 20-50% augmentation of colony formation in response to macrophage colony-stimulating factor (M-CSF), the macrophage-specific growth factor. One pathway is compatible with mediation by cGMP, the other with mediation by adenosine 3':5' cyclic monophosphate (CAMP). The cGMP pathway is activated by lipopolysaccharide (LPS) and/or host BRMs linked to increased levels of intracellular cGMP, e.g. tuftsin, substance P, leukotriene B₄. prostaglandin F_2alpha;, and atrial natriuretic peptide. Primary stimulation by LPS or the host agents is mediated by TNF_alpha; production and subsequent NO generation. These two agents are necessary in combination for augmented colony formation that is apparently dependent on the production of cGMP from soluble guanylyl cyclase. The cGMP pathway is inhibited by a 30kDa monokine produced by adherent marrow cells and by peptide mimics of the monokine. These inhibitory agents affect the proliferative pathway at a point after NO generation, perhaps by altering NO induced elevation of intracellular cGMP levels. Stimulation by cGMP is not affected by the inhibitors. In total, these findings describe two pathways capable of augmenting the production of monocytes and macrophages from precommitment bone marrow progenitors during host inflammatory responses. In addition to these findings, evidence is presented in support of an extracellular binding site for cAMP on murine bone marrow progenitors and of a role for the inhibitor in the modulation of endotoxin shock, a pathological condition associated with overproduction of IL-1, TNF_alpha;, and NO.

Recommended Citation

Detrick, Melinda S., "A mechanistic investigation of imflammatory murine monocytopoiesis. " PhD diss., University of Tennessee, 1994.
https://trace.tennessee.edu/utk_graddiss/10335