Fibrosarcoma-induced Dysregulation of Interleukin (IL)-1β and IL-18 Activities and their Modulation by Paclitaxel

Cancer remains an elusive killer due, in part, to the suppression of normal immunologic antitumor responses. Normal host (NH) macrophage (Mϕ) populations have tumoricidal effects such as tumor antigen phagocytosis and presentation, and cytokine production. Tumor-infiltrating Mϕs may evade these activities by dysregulating production of immunostimulatory cytokines (including Interleukin [IL]-1β, IL-18, and tumor necrosis factor-α [TNF-α]), by production of antagonistic factors. The restoration of IL-1β, IL-18, and TNF-α production by Mϕs could re-establish antitumor host immune responses. Previous work in our laboratory suggests that tumor distal (TD) Mϕs produce more IL-1β than NH Mϕs when stimulated with IFN-γ and lipopolysaccharide (LPS). We hypothesize that the presence of immunomodulatory factors like IL-10 and TGF-β dysregulate IL-1β production in tumor proximal (TP) Mϕs. Indeed, IL-1β production was downregulated among in situ TP Mϕs. We have proposed that IL-18, a structural homologue to IL-1β was similarly dysregulated in TD and TP Mϕs. IL-18 was enhanced in both distal and proximal Mϕs. Differences in the functions of these cytokines could account for this dissimilarity. TNF-α, another proinflammatory cytokine, followed the dysregulation pattern of IL-1β in our tumor-burdened hosts (TBH), likely because of the similar functions of these cytokines. Because it is a potential vehicle for immunotherapeutic treatment, paclitaxel's action on the immune response (TAXOL™) was investigated. Paclitaxel is a potent Mϕ activator that upregulates a variety of cytokines in an LPS-like manner. Paclitaxel enhanced TD Mϕ production of IL-1β, IL-18, and TNF-α in an LPS-like manner. Production of IL-1β and TNF-α was reduced in TP Mϕs when treated with paclitaxel; however, IL-18 production was enhanced. This difference could be due to the different functions of IL-1β and IL-18. To determine whether production of these cytokines translates into downstream expression of transcription products, IL-12 and nitric oxide (NO) were assayed. NO was enhanced distally, but paclitaxel treatment failed to enhance NO production. When treated with paclitaxel, IL-12 was produced by NH and TD Mϕs. Collectively, these studies suggest that tumor-induced cytokine imbalances compromise antitumor immunity and paclitaxel may reverse this activity.

Name thesis:degree_name

Master of Science

Level thesis:degree_level

masters

Discipline thesis:degree_discipline

Biology

Department dc:contributor.department

Biology

Grantor dc:publisher

Virginia Tech

Year dc:date.issued

2005

Author dc:creator

• Falwell, Elizabeth Paige

Chair dc:contributor.committeechair

• Elgert, Klaus D.

Committee members dc:contributor.committeemember

• Gogal, Robert M. Jr.
• Burger, Carol J.

• paclitaxel
• IL-12
• fibrosarcoma
• IL-1β
• NF-κB
• nitric oxide
• IL-18

Statement dc:rights

• In Copyright

Licence dc:rights.uri

• http://rightsstatements.org/vocab/InC/1.0/

Dc Identifier Other

etd-06152005-135205

OAI identifier oai:identifier

oai:vtechworks.lib.vt.edu:10919/33588