Compromised anti-tumor responses in tumor necrosis factor-α knockout mice

192

141

A growing body of knowledge is revealing the critical role of circadian physiology in the development of specific pathological entities such as cancer. NK cell function participates in the immune response against infection and malignancy. We have reported previously the existence of a physiological circadian rhythm of NK cell cytolytic activity in rats, suggesting the existence of circadian mechanisms subjacent to NK cell function. At the cellular level, circadian rhythms are originated by the sustained transcriptional-translational oscillation of clock genes that form the cellular clock apparatus. Our aim in this study was to investigate the presence of molecular clock mechanisms in NK cells as well as the circadian expression of critical factors involved in NK cell function. For that purpose, we measured the circadian changes in the expression of clock genes (Per1, Per2, Bmal1, Clock), Dbp (a clock-controlled output gene), CREB (involved in clock signaling), cytolytic factors (granzyme B and perforin), and cytokines (IFN-γ and TNF-α) in NK cells enriched from the rat spleen. The results obtained from this study demonstrate for the first time the existence of functional molecular clock mechanisms in NK cells. Moreover, the circadian expression of cytolytic factors and cytokines in NK cells reported in this study emphasizes the circadian nature of NK cell function.

Section: Discussionmentioning

confidence: 99%

Circadian Oscillations of Clock Genes, Cytolytic Factors, and Cytokines in Rat NK Cells

Arjona

Sarkar

2005

192

141

“…However, IFN-␥ is not the sole effector molecule produced by the activated NK cells to confer antitumor immunity. It has been reported that NKT cell-dependent activation of NK cells may also result in enhanced perforin and TNF-␣ production (4,13,64), both of which may, additionally to IFN-␥, confer antitumor immunity (5,13). Therefore, it will be important not only to determine the nature of signals that activate NKT cells, i.e., whether they are either tumor cell dependent (i.e., glycolipid ligands) or independent (e.g., cytokines), but also the signals that regulate the outcome of NKT function to be able to manipulate immune responses toward effective tumor destruction.…”

Section: Discussionmentioning

confidence: 99%

“…4). In addition, resting or unstimulated NK cells constitutively express a number of cytokine receptors and may be activated for increased cytotoxicity or cytokine production following stimulation by numerous cytokines (e.g., TNF-␣, IL-1, IL-2, IL-12, IL-15, IL-18, or IL-21) (3)(4)(5)(6)(7)(8)(9)(10). NKT cells constitute a lymphocyte subpopulation that expresses TCR and NK markers (NK1 or NKR-P1A) and have been implicated in immunoregulatory roles, as well as in controlling tumor growth (for review, see Ref.…”

mentioning

confidence: 99%

In Vivo Antitumor Activity of NKT Cells Activated by the Combination of IL-12 and IL-18

Baxevanis

Gritzapis

Papamichail

2003

Self Cite

Interleukin-12 and IL-18 have been demonstrated to potentiate innate immunity in a variety of experimental tumor models, but the functional roles of NK and/or NKT cells and their mechanism of action in these models have not been fully addressed. Through adoptive transfer of NKT cells activated in vitro with a combination of IL-12 plus IL-18 (IL-12/IL-18 NKT) into syngeneic animals, we demonstrate in this study that IL-12/IL-18 NKT cells are essential and collaborate with the host’s own NK cells in natural host immunity against the growth of ALC and MC57X syngeneic tumors. The relative roles of the adoptively transferred IL-12/IL-18 NKT cells and endogenous NK cells in host protection were first shown in normal C57BL/6 (B6) mice treated with anti-asialo GM1 Ab that selectively depletes NK cells; second, in B6.TCRJα281−/− mice specifically deficient for NKT cells; and third, in B6.scid mice that also lack NKT cells. Furthermore, by injecting normal B6 mice with anti-IL-2 and/or anti-IFN-γ mAb, we could demonstrate that effective innate immunity against both types of syngeneic tumors was dependent on the production of IL-2 and IFN-γ by the adoptively transferred NKT cells. In vitro studies confirmed both the secretion of IL-2 and IFN-γ by the IL-12/IL-18-activated NKT cells and their collaborative role with NK cells for lysis of ALC and MC57X syngeneic tumor targets. This is the first description of an antitumor function of IL-12/IL-18 NKT cells adoptively transferred into syngeneic hosts that provides the basis for a new modality in the cellular immunotherapy of cancer.

“…Although the use of the perforin/granzyme pathway appears to predominate, NK cells have been shown to use both Fas/FasL (7,12) and TRAIL-R/TRAIL (9,51) interactions to mediate cytotoxicity of tumor cells. Signaling through the TNF receptor can also be a potent NK cell cytotoxic component in the lysis of virally infected cells (52) and tumor cells (53). These findings illustrate the importance of these death receptors in target cell apoptosis by NK cells.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Death Receptor Pathway by cFLIP Confers Partial Engraftment of MHC Class I-Deficient Stem Cells and Reduces Tumor Clearance in Perforin-Deficient Mice

Taylor

Chaudhary

Klem

et al. 2001

NK cells mediate acute rejection of MHC class I-deficient bone marrow cell (BMC) grafts. However, the exact cytotoxic mechanisms of NK cells during acute BMC graft rejection are not well defined. Although the granule exocytosis pathway plays a major role in NK cell-mediated rejection, alternative perforin-independent mechanisms also exist. By analyzing the anti-apoptotic effects of cellular Fas-associated death domain-like IL-1-converting enzyme-inhibitory protein (cFLIP) overexpression, we investigated the possible role of death receptor-induced apoptosis in NK cell-mediated cytotoxicity. In the absence of perforin, we found that cFLIP overexpression reduces lysis of tumor cells by NK cells in vitro and in vivo. In addition, perforin-deficient NK cells were impaired in their ability to acutely reject cFLIP-overexpressing TAP-1 knockout stem cells. These results emphasize the importance of NK cell death receptor-mediated killing during BMC grafts in the absence of perforin.