This web page was designed for an undergraduate immunology course at Davidson College.
Structure and origin
Il-12 is a heterodimer composed of 2 subunits p35 and p40 that are encoded by separate genes.† Il-12 is produced mainly by macrophages/monocytes and can be elicited by intracellular parasites, bacteria, and bacterial components.† Active Il-12 requires the expression of both subunits.† The subunit p35 is also called Il-12 a, cytotoxic lymphomaturation factor 35kD subunit (CLMF p35), or NK cell stimulatory factor chain 1 (NKSF1).† The p40 subunit is also called Il-12 b, cytotoxic lymphomaturation factor 40kD subunit (CLMF p40), or NK cell stimulatory factor chain 2 (NKSF2) http://184.108.40.206/treatment/drug/ID268.asp.
††††††††††† Interleukin-12 regulates T-cell and natural killer-cell responses, induces the production of interferon-g.† It also favors the differentiation of T helper cells and is a vital link between innate resistance and adaptive immunity.† Phagocytes were thought to be the only cells that produced Il-12 but now it is know that certain dendritic cells are the first to secret the cytokine (Trinchierei 2003).†††††††††
Disease related disorders
Crohnís disease is an inflammatory disease of the gut in which tumor necrosis factor (TNF) and IL-12 and IFN -g are implicated in the origin.† Studies have shown that anti-TNF therapies are beneficial for the treatment of this disease.† Recent studies on anti-IL-12 pro-inflammatory cytokines have been shown not to influence the production of TNF.† Therefore therapies for Crohnís disease using the neutralization of IL-12 are not a viable method (Colpaert S et al 2002).
††††††††††† Il-12 has been implicated in the development of TH1 cells.† It has been postulated that a Th1 response during pregnancy precedes the failure of pregnancy.† Recent studies have shown that this is not necessarily true (Zenclussen et al. 2002).†
Figure 1.† This image was taken from www.cogs.csustan.edu/~tom/bioinfo/groupwork/interleukin/interleukin.ppt .† This figure shows the secondary structure of Il-12.† Notice the repeating structural motifs of alpha-helices and random coil.† Permission is pending.
The use of immunostimulatory molecules like Il-12 as tumor vaccines has become a promising strategy in cancer immunotherapy.† It is well know that cytokines like Il-12 activate Th1 responses.† The goal of these therapies is to activate tumor specific cytotoxic T-cells capable of destroying tumor cells. Efficacy has been shown in models that provide high levels of immunostimulatory molecules like Il-12 (Mackensen et al., 1997).† Il-12 has not only been implicated in the eradication of tumors but as well as in the reduction of metastases in various tumor models (Hiscox and Jiang 1997).
††††††††††† Il-12 administration has been shown to help reduce growth of colon carcinoma in certain in vivo models.† When given to animals in does around 500ng-1000ng/animal over a six-day period Il-12 has been reported to reduce the volume of tumor growth within 12 days (Liu L, et al 2003).††
Mechanism of Clinical Application
The ability to elicit Th1 responses accounts for the ability of Il-12 to promote tumor regression.† It is the response of NK cells and cytotoxic T-cells that cause the regression of the tumors.† Il-12ís antitumor properties have also been attributed to its ability to inhibit angiogenesis, thereby effectively cutting off the tumorís nutrient supply (Sun et al., 1998).
IL-12 has been shown to have very strong anti-angiogenesis properties.† Il-12 when administered with vasostatin has been shown to halt tumor growth in human Burkitt lymphoma, colon carcinoma, and ovarian carcinoma. Also anti-tumor effects have demonstrated.† Studies have shown that FTL-3 ligand and Interleukin-12 have a dose dependent additive anti-tumor effect mediated by NK cells against human ovarian cancer in SCID mouse.† Efficacy has been demonstrated against ovarian cancer cell lines and ascites ( http://www.slip.net/~mcdavis/il12.html).
Sun, Y., et al. (1998).† Vaccination with Il-12 gene-modified autologous melanoma cells: preclinical results and first clinical phase I study. Gene Ther. 5: 481-490.
Hiscox, S. and Jiang W.G. (1997). Interleukin-12 , an emerging anti-tumor cytokine. In Vivo 11:125-132.
Mackensen, A., et al. (1997) Immunostimulatory cytokines in somatic cells and gene therapy of cancer. Cytokine Growth Factor Re. (1997) 8:119-128.†††
Colpaert S, Vastraelen K, Liu Z, Maerten P, Shen C, Pennickx F, et al.† Oct-Dec. 2002.† In Vitro analysis of IGN-g and Il-112 production and their effect in ileal Crohnís disease.† Eur Cytokine Netw. 13(4) 431-7.
Liu L, sakaguchi T, Kanda T, Hitomi J, Tabata Y, Hatakayema K.† 2003.† Delivery of interleukin-12 in gelatin hydrogels effectively suppresses development of transplanted colonal carcinoma in mice.† Cancer Chemother Pharmacol.† 51(1):53-57.
Trinchieri, Giorgio. 2003.† Interleukin-12 and the regulation of innate resistance and adaptive immunity.† Nature Reviews Immunology. 3: 133-146.
Zenclussen AC, Fest S, Busse P, Joachin R, Klapp BF. 2002. Questioning the Th1/Th2 paradigm in reproduction: peripheral levels of Il-12 are down regulated in miscarriage patients. Am J Reprod Immunol 48 (4):245-251
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