Molecular characterization of interleukin 12

Podlaski, Frank J.; Nanduri, Venkata; Hulmes, Jeffrey D.; Pan, Yu‐Ching E.; Levin, Wayne; Danho, Waleed; Chizzonite, R; Gately, Maurice K.; Stern, Alvin S.

doi:10.1016/0003-9861(92)90162-p

Cited by 95 publications

(50 citation statements)

References 20 publications

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“…This proinflammatory cytokine is mainly produced by activated dendritic cells, monocytes, and keratinocytes (KC) 2 (1)(2)(3)(4). Apart from its capacity to enhance proliferation and cytotoxicity of T and NK cells, IL-12 commits differentiation of naive CD4 and CD8 T cells to cells that preferentially produce IFN-␥ and IL-2 (T1 cells) (5,6).…”

Section: Il-23 Production By Cosecretion Of Endogenous P19 Andmentioning

confidence: 99%

IL-23 Production by Cosecretion of Endogenous p19 and Transgenic p40 in Keratin 14/p40 Transgenic Mice: Evidence for Enhanced Cutaneous Immunity

Kopp

Lenz

Bello-Fernández

et al. 2003

The Journal of Immunology

124

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p40, the common subunit of the proinflammatory cytokines IL-12 and IL-23, is produced by resident skin cells. Whereas the in vivo effects of IL-12 are well established, little is known about the role of IL-23 in cutaneous immune responses. In this study we show that p40 transgenic (TG) mice constitutively produce IL-23 (p19/p40), but not IL-12 (p35/p40), in basal keratinocytes by cosecretion of TG p40 with endogenous p19. Repeated injections of rIL-23 in littermate (LM) mice result in an inflammatory skin disease similar to that of p40 TG mice, confirming the proinflammatory activity of IL-23. Furthermore, IL-23 secretion by p40 TG keratinocytes induces elevated numbers of Langerhans cells (LC) with a marked up-regulation of costimulatory molecules, indicating advanced maturation of keratin 14 (K14)/p40 LC when compared with LM LC. At the functional level, freshly isolated K14/p40 LC greatly exceeded LC from LM animals in their capacity to stimulate allogeneic T cell proliferation. To assess whether IL-23 regulates cutaneous immune responses in vivo, we used an allogeneic skin transplantation model. Full thickness skin grafts from K14/p40 donors (H-2q) transplanted across a MHC class I and class II barrier onto BALB/c (H-2d) recipients were rejected in a significantly accelerated fashion (mean survival time: 8.8 days) when compared with skin grafts from non-TG LM (H-2q) (mean survival time: 10.7 days, p < 0.01). Based on these results we propose that IL-23-induced changes of LC may be an important mechanism in directing the outcome of cutaneous immune responses.

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Section: Il-23 Production By Cosecretion Of Endogenous P19 Andmentioning

confidence: 99%

IL-23 Production by Cosecretion of Endogenous p19 and Transgenic p40 in Keratin 14/p40 Transgenic Mice: Evidence for Enhanced Cutaneous Immunity

Kopp

Lenz

Bello-Fernández

et al. 2003

The Journal of Immunology

124

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“…IL-12 is a heterodimer composed of both p35 and p40 subunits. The smaller subunit is required for signaling through the IL-12 receptor, whereas the larger subunit facilitates protein binding (7). The demonstration of significant antitumor activity in several preclinical animal models has piqued interest in the therapeutic use of IL-12 (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Interleukin-12 Up-Regulates Fas Expression in Human Osteosarcoma and Ewing's Sarcoma Cells by Enhancing Its Promoter Activity

Zhou

Lafleur

Koshkina

et al. 2005

Molecular Cancer Research

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Interleukin-12 (IL-12) has shown significant antitumor activity in several preclinical animal tumor models. Our previous studies showed that IL-12 inhibited tumor growth in human osteosarcoma and Ewing's sarcoma animal model. Decreased Fas expression in osteosarcoma increased the lung metastatic potential. In this study, we further examined the mechanism of IL-12 antitumor activity and showed that IL-12 significantly increased Fas expression in both human osteosarcoma cells LM7 and Ewing's sarcoma cells TC71. Up-regulation of Fas expression increased their sensitivity to Fas-induced cell apoptosis. Constructs of the Fas promoter linked to a luciferase reporter gene were used to determine the promoter activity. IL-12 increased Fas promoter activity 4.2-and 4.9-fold in TC71 and LM7 cells, respectively. Time course studies have shown that recombinant IL-12 stimulated Fas promoter activity at 2 hours, reached the peak level at 4 hours, and then declined at 24 hours. To investigate whether IL-12 specifically enhanced Fas promoter activity, we determined whether another gene (E1A) was able to stimulate Fas promoter activity. We also evaluated effect of IL-12 on the topoisomerase IIA promoter. The results indicated that E1A but not IL-12 stimulated topoisomerase IIA promoter activity. E1A failed to increase Fas promoter activity. We also found that KB-Sp1 element at position À295 to À286 in Fas promoter was essential for IL-12-induced activation, and nuclear factor-KB transcription factor was activated after IL-12 treatment in TC71 cells. These results indicate that IL-12 up-regulates Fas expression in human osteosarcoma and Ewing's sarcoma by enhancing Fas promoter activity.Understanding this mechanism may lead to new therapeutic approaches for the treatment of sarcoma involving the use of IL-12. (Mol Cancer Res 2005;3(12):685 -91)

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“…The p40 subunit can be secreted as a monomer, or a homodimer, as well as a form of either an IL-12 or IL-23 heterodimer (11). The production of IL12p40 monomer or homodimer is in large excess over IL-12 in vitro (12)(13)(14) and in vivo (15), and IL-12p40 monomer is produced more abundantly than homodimeric IL-12p40 (p80) by ϳ2 to 5-fold (16,17). However, the monomer binds to IL-12 receptor with only low affinity, whereas the homodimer has higher binding affinity to the receptor (13,17,18).…”

mentioning

confidence: 99%

Differential Regulation of Antigen-Specific CD8+ T Cell Responses by IL-12p40 in a Dose-Dependent Manner

Kim

Youn

Seo

et al. 2008

The Journal of Immunology

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IL-12p40 is a natural antagonist which inhibits IL-12- and IL-23-mediated biological activity by blocking the binding of IL-12/23 to their receptors. Recently, IL-12p40 was also shown to have immune-enhancing activity through the activation of macrophages or dendritic cells. In this study, we investigated the effects of IL-12p40 as a genetic adjuvant on immune modulation using recombinant adenoviruses expressing IL-12p40 (rAd/IL-12p40) and OVA (rAd/OVA). Coimmunization of rAd/IL-12p40 at a low dose (1 × 104 PFU) with rAd/OVA resulted in OVA-specific immune enhancement, while a high dose of rAd/IL-12p40 (1 × 108 PFU) caused significant suppression of CD8+ T cell responses. In addition, the enhancement and suppression of OVA-specific CD8+ T cell responses correlated with antitumor activity against E.G7-OVA tumor challenge, which subsequently affected the survival rate. Moreover, the differential CD8+ T cell response by IL-12p40 was still observed in IL-12Rβ2 knockout (IL-12Rβ2KO), but not in IL-12Rβ1 knockout (IL-12Rβ1KO) mice, indicating that IL-12p40 is a cytokine which can modulate Ag-specific T cell responses depending on IL-12Rβ1. Our findings provide a novel insight on the physiological role of IL-12p40, which can be informative in the design of vaccine strategies and therapeutic regimens.

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Molecular characterization of interleukin 12

Cited by 95 publications

References 20 publications

IL-23 Production by Cosecretion of Endogenous p19 and Transgenic p40 in Keratin 14/p40 Transgenic Mice: Evidence for Enhanced Cutaneous Immunity

IL-23 Production by Cosecretion of Endogenous p19 and Transgenic p40 in Keratin 14/p40 Transgenic Mice: Evidence for Enhanced Cutaneous Immunity

Interleukin-12 Up-Regulates Fas Expression in Human Osteosarcoma and Ewing's Sarcoma Cells by Enhancing Its Promoter Activity

Differential Regulation of Antigen-Specific CD8+ T Cell Responses by IL-12p40 in a Dose-Dependent Manner

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