IL-6 and Stat3 Are Required for Survival of Intestinal Epithelial Cells and Development of Colitis-Associated Cancer
Volume 15, Issue 3, 3 March 2009, Page 241,
Sergei Grivennikov, Eliad Karin, Janos Terzic, Daniel Mucida, Guann-Yi Yu, Sivakumar Vallabhapurapu, Jürgen Scheller, Stefan Rose-John, Hilde Cheroutre, Lars Eckmann, Michael Karin
Summary:
Colitis-associated cancer (CAC) is the major cause of death for ulcerative colitis patients around the world. Chronic inflammation release compounds that affect the growth and survival of cells. Previous studies have suggested that inflammation effects acts as tumor promoters. Immune cells produce cytokines and chemokines that propagate localize inflammatory responses that activate transcription factor, NF-kB. NF-kB enhance the growth and survival of premalignant cells. In cases of CAC, NF-kB-driven cytokine production by myeloid cells play an active role of CAC development . For intestinal epithelial cells (IEC), NF-kB activation produces cytokines that promote the survival and growth of premalignant cells created during the early phase of CAC tumorigensis.
In this paper, the identity of this cytokine produced by the NF-kB activation in myeloid cells is explored. Using CAC-induced mice, the ablation of the interleukin 6 (IL-6) cytokine produced by NF-kB was studied. This deficiency of IL-6 lowered the tumors in mice. The IL-6 decreased the tumor multiplicity in mice that suggests the role of IL-6 could be in early tumor promotion. The study examined the possible proliferation of intestinal epithelial cells (IECs) due to IL-6. IEC proliferation was enhanced by IL-6 as well as the apoptosis of IEC was lowered by IL-6 as well. With the regulation of IEC, the study continued to understand the cell source of IL-6 during tumorigenesis. Using bone marrow, the study results showed that Lamina propria and tumor-infilitrating CD11c+ (dendritic cells) CD11b+ (macrophages) are the major producers of IL-6 and then CD3+ (T cells) produce some IL-6 during CAC development. Within the same study, IL-6 was determined to be an important factor for tumor growth as well expression of genes required for premalignant cells during CAC tumorigenesis. The consequence of IL-6 deficiency resulted in the deficiency of phosphorylated Stat3. Stat3 is an activator of IECs during tumor growth. The absence of Stat3 in IEC disturbs the the tumor formation and growth of CAC. Thus, IL-6 major effect is the deficiency of Stat3. The cascade of NF-kB-IL-6-Stat3 is crucial to the development of tumor and growth of CAC.
The significance of this work is the identification of cytokines involved with tumor development and proliferation. Malignant cells survive through cytokines produced by inflammatory cells. Previous studies have shown that NF-κB activation in myeloid cells stimulate growth of premalignent intestinal epithelial cells (IEC) in colitis-associated cancer (CAC). This paper identifies NF-κB-dependent cytokine, IL-6 as the source for stimulus of premalignant IEC to survive and develop. The oncogenic transcription factor STAT3 mediates the effects of IL-6. Thus IL-6 and STAT3 could be targeted for future prevention and treatment of CAC
6 comments:
It seems that IL-6 plays a dual role here when you say that a deficiency of IL-6 lowered the tumors in mice, but that IL-6 also decreased tumor multiplicity. How can the presence and absence of IL-6 both decrease tumor growth?
As the paper suggests, IL-6 may play important role only in early tumor promotion. Maybe we can think of it as both the activator and suppressor at the same time: be crucial at the beginning but too much later can cause deficiency.
What other role does IL-6 have in physiological system? Although lowering IL-6 may decrease tumor proliferation, will it have any other effect on body, such as, disturbing the immune response?
If IL-6 plays a dual role and Stat3 is required for tumor survival, are there other ways to cause deficiency of Stat3?
What are the exact functions of dendritic cells? Are those the neural cells or something? If so, why do you think that the major sources of IL-6 are dendritic cells, which may belong to the neural system and t-cells, which belong to the immune system? It just seems odd to me that seemingly very different systems in the body produce the same compound.
Dendritic cells are immune cells. Thus, it makes sense for IL-6 to be part of the immune system.
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