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PubMed2003

IL-23 production by cosecretion of endogenous p19 and transgenic p40 in keratin 14/p40 transgenic mice: evidence for enhanced cutaneous immunity.

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-2(q)) transplanted across a MHC class I and class II barrier onto BALB/c (H-2(d)) recipients were rejected in a significantly accelerated fashion (mean survival time: 8.8 days) when compared with skin grafts from non-TG LM (H-2(q)) (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.

Animals↗
PubMed1993

Cloning and sequence analysis of a p40 structural protein gene of Helicoverpa zea nuclear polyhedrosis virus.

A gene encoding an occluded virion structural protein was isolated from an expression library constructed from the Helicoverpa zea S-type nuclear polyhedrosis virus (NPV) isolate HzS-15 using both polyclonal and monoclonal antibody screening. The gene was located within a Pstl-Sall fragment of the HzS-15 genome spanning from 96.5 to 97.3 m.u. Sequencing analyses revealed a long open reading frame of 927 nucleotides that predicted a protein of 37 kDa in size. Immunoblot analyses using the monoclonal antibody ENV409 demonstrated that the gene corresponded to a 40-kDa protein (p40) in SDS-polyacrylamide gels that was present exclusively in enveloped occluded virions but not in extracellular budded virions or envelope-stripped nucleocapsids. A p40 protein-specific transcript was detected at 16 hr postinfection in HzS-15-infected Hz 1075/UND-K cells and remained until 22 hr. Primer extension analyses demonstrated that the p40 protein-specific transcript started at -49 nucleotides from the ATG start codon within an ATAAG consensus pentamer found in late protein genes of Baculoviruses. The deduced amino acid sequence of the HzS-15 p40 protein gene shared 44 and 45% sequence homology with the p40 proteins of Bombyx mori NPV and Autographa californica NPV, respectively.

Amino Acid Sequence↗
PubMed1992

Anti-infectious effect of C granulosum-derived P40 immunomodulator given by aerosolization and intranasal instillation.

It is known that C granulosum-derived P40 immunomodulator displays strong anti-microbial effects in mice by the intravenous route. Since microbial contamination of humans occurs in many instances via the airways, the effect of P40 on infections was investigated when it was given intranasally or by aerosolization. In order to augment its bioavailability, P40 was derivatized by coupling with polylysine chains (P40-PL). The results showed that P40-PL exercised a significant protective effect, both by the intranasal route and by aerosolization on both influenza and K pneumoniae infections produced by aerosolization or intranasal instillation. Stimulation of the phagocytic capacity of alveolar macrophages by these types of treatment is likely to account for the increased resistance of mice toward microbial infections.

Adjuvants, Immunologic↗
PubMed2005

Interleukin-12 p40 promoter activity is regulated by the reversible acetylation mediated by HDAC1 and p300.

Interleukin-12 (IL-12) is a heterodimeric cytokine produced by macrophages in response to intracellular pathogens. The importance of IL-12 in generation of Th1 response against human pathogens has been characterized. The coactivator p300 is an important histone acetyltransferase (HAT) and has been implicated in the regulation of many genes. Histone deacetylases (HDACs) regulate gene transcription through deacetylation of histones. Whether the reversible histone acetylation/deacetylation modification participates in the regulation of IL-12 p40 transcription expression has not been investigated before. In this study, we analyzed the roles of HDAC1 and p300 in the regulation of human IL-12 p40. Co-transfection studies showed that HDAC1 had a repressing effect on the activity of IL-12 p40 promoter. Contrarily, p300 was able to reinforce the C/EBPbeta-mediated activation of IL-12 p40 and it counteracted the HDAC1-mediated repression of the IL-12 promoter. Chromatin immunoprecipitation tests (ChIP) revealed that p300 had a stimulating effect on the acetylation of the histone H3 at IL-12 p40 promoter. In addition, we showed that p300 had a physical interaction with C/EBPbeta and can enhance acetylation of C/EBPbeta. Data presented in this paper indicate that the reversible histone acetylation/deacetylation modification plays an important role in the transcriptional regulation of IL-12.

Acetylation↗
PubMed2005

Analysis of potential binding of the recombinant Rab9 effector p40 to phosphoinositide-enriched synthetic liposomes.

The transport factor p40 is thought to assist Rab9 in mediating late-endosome-to-TGN vesicular transport. p40 was recently identified as an associated protein of the PtdIns 5-P/PtdIns 3,5-P2-producing kinase PIKFyve. Moreover, p40 recovery in membrane fractions appeared totally dependent on the presence of an intact enzymatic activity of PIKFyve, implying a mechanism of p40 membrane association dependent on membrane PtdIns 5-P and/or PtdIns 3,5-P2. Here we have evaluated plausible interaction of recombinant p40 with the PIKFyve products PtdIns 5-P and PtdIns 3,5-P2 by a synthetic-liposome binding assay.

Base Sequence↗
PubMed1999

Early IL-12 p70, but not p40, production by splenic macrophages correlates with host resistance to blood-stage Plasmodium chabaudi AS malaria.

In this study, we compared synthesis of IL-12, a potent Th1-inducing cytokine, by splenic macrophages recovered from resistant C57Bl/6 (B6) mice, which develop predominantly Th1 responses, and susceptible A/J mice that mount primarily Th2 responses during early Plasmodium chabaudi AS infection. Quantitative analysis of IL-12 p40 and p70 release by ELISA revealed significant differences between resistant B6 and susceptible A/J mice in the synthesis of biologically active IL-12 p70, but not p40, by splenic macrophages during early blood-stage P. chabaudi AS infection. Despite up-regulation in p40 and p35 mRNA levels, spontaneous release of p40 in vitro by splenic macrophages was not significantly increased following infection in either mouse strain. In contrast, spontaneous release of p70 by splenic macrophages was increased in cells from B6 mice and levels were significantly higher compared with A/J mice. Furthermore, compared with infected A/J hosts, splenic macrophages recovered from infected B6 mice produced significantly greater quantities of IL-12 p70, but not p40, in vitro, following stimulation with lipopolysaccharide (LPS) or malaria parasite antigen (PRBC). Moreover, we found significant increases in the percentage of macrophages earlier in the spleens of infected B6 mice that could further contribute to differences in total p70 levels in vivo. Taken together, these data suggest that macrophage IL-12 synthesis may contribute to the polarization of Th responses seen in resistant B6 and susceptible A/J mice during acute blood-stage malaria.

Acute Disease↗
PubMed2000

Selective requirement for c-Rel during IL-12 P40 gene induction in macrophages.

A major challenge in the study of gene regulation by NF-kappaB/Rel transcription factors is to understand, at the biological and mechanistic levels, the selective functions of individual Rel family members. To study selectivity, we have examined the NF-kappaB/Rel protein binding site (Rel site) within the IL-12 p40 promoter. IL-12 is a proinflammatory cytokine expressed by activated macrophages that serves as an essential inducer of T helper 1 cell development. In nuclear extracts from lipopolysaccharideactivated macrophages, the predominant Rel dimers capable of binding the IL-12 p40 Rel site were the p50/p65 and p50/c-Rel heterodimers and p50/p50 homodimer. The two heterodimers bound the site with comparable affinities and exhibited comparable transactivation activities. In striking contrast, p40 mRNA and protein concentrations were reduced dramatically in c-Rel(-/-) macrophages and only modestly in p65(-/-) macrophages. Other proinflammatory cytokine mRNAs and proteins were not significantly reduced in c-Rel(-/-) macrophages. These results reveal that a c-Rel-containing complex is an essential and selective activator of p40 transcription, which may reflect unique regulatory mechanisms or biological functions of IL-12. Furthermore, because selectivity was not observed in vitro or in transient transactivation experiments, these findings suggest that an understanding of the selectivity mechanism may require an analysis of the endogenous p40 locus.

Animals↗
PubMed1998

Synergistic regulation of the human interleukin-12 p40 promoter by NFkappaB and Ets transcription factors in Epstein-Barr virus-transformed B cells and macrophages.

Monocytes/macrophages produce interleukin-12 (IL-12) in response to pathogenic stimulation, whereas most Epstein-Barr virus-transformed (EBV+) B cells constitutively secrete IL-12. The molecular mechanism regulating the constitutive IL-12 gene expression in EBV+ B cells has not been addressed. In this study, using the EBV+ B cell line RPMI-8866, we localized to the human IL-12 p40 promoter two essential cis elements, the NFkappaB site and the Ets site. The NFkappaB site was shown to interact with members of the NFkappaB family: p50 and c-Rel. The Ets site constitutively bound a multi-component Ets-2-containing complex. While the NFkappaB and Ets sites appear equally critical for inducible p40 promoter activity in macrophage cell lines, NFkappaB plays a more dominant role in the constitutive p40 promoter activity in EBV+ B cells. Transient expression of Ets-2 and c-Rel in B, T, and monocytic cell lines synergistically activated the IL-12 p40 promoter, apparently overcoming the requirement for cell type- or stimulant-specific transcription factors. These data provide new evidence that full activation of the human IL-12 p40 promoter may result primarily from the interplay between NFkappaB and Ets family members.

B-Lymphocytes↗
PubMed1997

Interferon consensus sequence binding protein-deficient mice display impaired resistance to intracellular infection due to a primary defect in interleukin 12 p40 induction.

Mice lacking the transcription factor interferon consensus sequence binding protein (ICSBP), a member of the interferon regulatory factor family of transcription proteins, were infected with the intracellular protozoan, Toxoplasma gondii. ICSBP-deficient mice exhibited unchecked parasite replication in vivo and rapidly succumbed within 14 d after inoculation with an avirulent Toxoplasma strain. In contrast, few intracellular parasites were observed in wild-type littermates and these animals survived for at least 60 d after infection. Analysis of cytokine synthesis in vitro and in vivo revealed a major deficiency in the expression of both interferon (IFN)-gamma and interleukin (IL)-12 p40 in the T. gondii exposed ICSBP-/- animals. In related experiments, macrophages from uninfected ICSBP-/- mice were shown to display a selective impairment in the mRNA expression of IL-12 p40 but not IL-1alpha, IL-1beta, IL-1Ra, IL-6, IL-10, or TNF-alpha in response to live parasites, parasite antigen, lipopolysaccharide, or Staphylococcus aureus. This selective defect in IL-12 p40 production was observed regardless of whether the macrophages had been primed with IFN-gamma. We hypothesize that the impaired synthesis of IL-12 p40 in ICSBP-/- animals is the primary lesion responsible for the loss in resistance to T. gondii because IFN-gamma-induced parasite killing was unimpaired in vitro and, more importantly, administration of exogenous IL-12 in vivo significantly prolonged survival of the infected mice. Together these findings implicate ICSBP as a major transcription factor which directly or indirectly regulates IL-12 p40 gene activation and, as a consequence, IFN-gamma-dependent host resistance.

Acute Disease↗
PubMed2006

Ovarian follicular concentration of IL-12, IL-15, IL-18 and p40 subunit of IL-12 and IL-23.

BACKGROUND: The aim of the study was to determine the presence of interleukin (IL)-12, IL-15, IL-18 and p40 subunit of IL-12/IL-23 in follicular fluid from spontaneous cycles and the relation between the concentration of selected cytokines and IVF-embryo transfer outcome. METHODS: IVF-embryo transfer and enzyme immunoassay (EIA) (R&D Systems, Minneapolis, MN, USA and MBL, Nagoya, Japan) were used. RESULTS: Follicular fluid of women included in the IVF-embryo transfer procedure contained common p40 subunit of IL-12/IL-23 (median 70.1 pg/ml), IL-15 (median 1.3 pg/ml) and IL-18 (median 38.2 pg/ml). There was a significant negative correlation between follicular fluid concentrations of IL-15 and IL-18 (R=-0.392, P=0.003). Significantly higher concentrations of common p40 subunit of IL-12/IL-23 (median 79.8 pg/ml) were found in the follicular fluid taken from follicles containing oocytes, when compared with those without an oocyte (median 44.5 pg/ml, P=0.006). Patients who achieved clinical pregnancy had significantly decreased concentration of IL-15 (median 0.8 pg/ml) compared with patients without successful IVF-embryo transfer outcome (median 1.4 pg/ml, P=0.047). CONCLUSION: Follicular fluid collected from spontaneous cycles contains detectable levels of p40 subunit of IL-12/IL-23, IL-15 and IL-18. Increased concentrations of p40 subunit of IL-12/IL-23 in follicles containing oocytes suggest an important role of this cytokine in reproduction. Possible negative value of IL-15 as a predictor of IVF-embryo transfer success remains to be determined.

Embryo Transfer↗
PubMed2000

Spermine differentially regulates the production of interleukin-12 p40 and interleukin-10 and suppresses the release of the T helper 1 cytokine interferon-gamma.

Polyamines are endogenous immunomodulatory molecules. Recent studies revealed that polyamines suppress the production of proinflammatory cytokines and nitric oxide. In the present study, we investigated the effect of the polyamines spermine, spermidine, and putrescine on the production of interleukin (IL)-12 p40, IL-10, and interferon (IFN-gamma) in mouse peritoneal macrophages and spleen cell suspensions. Spermine, but not spermidine or putrescine, suppressed, in a concentration-dependent manner, the production of IL-12 p40 by lipopolysaccharide (LPS)-stimulated macrophages. The effect of spermine was post-transcriptional, because steady-state levels of messenger ribonucleic acid (mRNAs) for IL-12 (p35 and p40) were not affected. In contrast to its inhibitory effect on IL-12 p40, spermine (0.3-3 microM) augmented IL-10 production. The down-regulation of IL-12 p40 by spermine was independent of enhancement of IL-10 by this agent, for spermine retained its ability to suppress IL-12 production in peritoneal macrophages obtained from IL-10-deficient mice. The alterations in cytokine production by spermine did not involve an effect on early intracellular pathways of LPS signal transduction, including the p38 or p42/44 mitogen-activated protein kinases, or the c-jun terminal kinase. In spleen cell suspensions, spermine suppressed the release of IFN-gamma induced either by LPS or anti-CD3 antibody. In summary, spermine exerts anti-inflammatory effects by suppressing IL-12 and IFN-gamma and by augmenting the production of IL-10.

Animals↗
PubMed1989

Complete amino acid sequence of a new murine T-cell growth factor P40.

A new murine T-cell growth factor, designated P40, which supports growth of helper T-cells in the absence of interleukin-2, interleukin-4 and antigen has been isolated from helper T-cell lines in sufficient quantities (100 micrograms) to permit its complete amino acid sequence determination. This was achieved by a combination of sensitive peptide mapping using microbore reversed-phase high performance liquid chromatography and automated microsequence analysis. Attempts to obtain N-terminal sequence data on P40 were unsuccessful due to N-terminal blockage of the native molecule. The nature of this N-terminal blocking was established using a combination of amino acid analysis, fast-atom-bombardment mass spectrometry and peptide synthesis. The P40 molecule, a single polypeptide chain comprising 126 amino acid residues, is structurally distinct from other known T-cell growth factors. No similarity was revealed when the amino acid sequence of P40 was compared with other proteins whose biochemical structure is known. The protein sequence data reported here predict four N-linked glycosylation sites in the P40 molecule.

Amino Acid Sequence↗
PubMed1992

Induction of various cytokines in mice and activation of the complement system in rats as a part of the mechanism of action of the Corynebacterium granulosum-derived P40 immunomodulator.

The capacity of the Corynebacterium granulosum-derived P40 immunomodulator to induce in mice the formation of various cytokines IFN, IL-1, IL-2, alpha-TNF as well as to activate the complement system in rats was investigated. The results showed that P40 injected by the intravenous route was capable of inducing the formation of all four cytokines. High levels of IFN were measured 2 h after P40 stimulation and were still present at 24 h. The kinetic study of IL-1, IL-2 and alpha-TNF induction showed that it was a biphasic phenomenon. The patterns of IL-1 and alpha-TNF induction were quite comparable, whereas the release of IL-2 was delayed with respect to that of IL-1 and alpha-TNF. Oral administration of P40 to rats strongly activated the alternative pathway of the complement system. It was concluded that most of the non-specific effects of P40 on the immune system are likely to be mediated by its capacity to induce cytokine formation and to activate the complement system.

Adjuvants, Immunologic↗
PubMed1992

Sequence similarity between Borna disease virus p40 and a duplicated domain within the paramyxovirus and rhabdovirus polymerase proteins.

We report the sequence of a Borna disease virus clone (pBDV-40) that encodes a 40-kDa protein (p40) found in the nuclei of infected cells. Comparative sequence analysis indicates that p40 is distantly similar to two different regions in the L-polymerase proteins encoded by paramyxoviruses and rhabdoviruses. The p40 sequence similarity indicates a previously undetected duplication in these viral polymerases. Phylogenetic reconstruction suggests that the gene that encodes p40 last shared a common ancestor with these viral polymerase genes prior to the duplication event. These findings support the hypothesis that Borna disease virus is a negative-strand RNA virus and suggest that p40 is involved in transcription and/or replication. The discovery of a duplication within the polymerase proteins of paramyxoviruses and rhabdoviruses has profound implications for the mapping of enzymatic activities within these multifunctional proteins.

Amino Acid Sequence↗
PubMed1997

Multiple control elements mediate activation of the murine and human interleukin 12 p40 promoters: evidence of functional synergy between C/EBP and Rel proteins.

Interleukin 12 (IL-12) is a heterodimeric cytokine whose activity is critical for T-helper 1 responses. The gene for the IL-12 p40 subunit is expressed in macrophages following induction by bacterial products, and its expression is augmented by gamma interferon. In this study, we performed a functional analysis of the murine and human p40 promoters in the murine macrophage cell line RAW 264.7. Transcription from the murine p40 promoter was strongly induced by lipopolysaccharide and heat-killed Listeria monocytogenes (HKLM), but promoter activity was not enhanced by gamma interferon. Multiple cis-acting elements involved in activated transcription were identified through an extensive mutant analysis. The most critical element, whose activity is conserved in mice and humans, is located between positions -96 and -88 relative to the murine transcription start site. This element exhibits functional synergy with a previously described NF-kappaB half-site which interacts with Rel proteins. DNase I footprinting and electrophoretic mobility shift assays demonstrated that C/EBP proteins interact with the critical element, but in nuclear extracts, cooperative binding of C/EBP and Rel proteins to their respective sites was not observed. Interestingly, promoter activity was induced by HKLM in the presence of cycloheximide, consistent with induction by posttranslational mechanisms. The results suggest that C/EBP and Rel proteins play important roles in the activation of IL-12 p40 transcription by bacteria. However, many complex interactions will need to be clarified to fully understand p40 regulation.

Animals↗
PubMed2003

Reduction of IL-12 p40 production in activated monocytes after exposure to diesel exhaust particles.

BACKGROUND: A reduction of IL-12 production by lung macrophages may partly explain the presumed adjuvant effect of diesel exhaust particles (DEP) in allergy and asthma. IL-12 stimulates T helper type 1 (Th1) lymphocytes, which inhibit Th2 cells via Th1-specific cytokines. The aim of this study was to investigate the influence of DEP on the production of IL-12 p40 in lipopolysaccharide (LPS)-activated monocytes. METHODS: The human monocytic cell line Mono-Mac-6 was stimulated with LPS (200 ng/ml) and grown with DEP (0-200 microg/ml) for 0, 6 or 24 h. IL-12 p40 and the pro-inflammatory cytokine TNF were analysed in the cell supernatants by ELISA and a cell assay, respectively. RESULTS: Levels of IL-12 p40 correlated inversely with the DEP exposure concentrations, whereas TNF increased in parallel to the DEP concentrations. At a DEP concentration of 200 microg/ml, the amount of IL-12 p40 was 35% of that observed without DEP. The corresponding TNF value was 230% of the control. Reduced viability, binding of cytokines to DEP or endotoxin in the DEP samples cannot fully explain the changes in the concentrations of these two cytokines. CONCLUSION: DEP seem to inhibit the production of IL-12 p40 and stimulate that of TNF in activated monocytes. This may partly explain the presumed adjuvant effect of DEP in atopy; by altering the Th1/Th2 balance via down-regulation of IL-12, the Th2 response characteristic of allergy and asthma may be favoured.

Asthma↗
PubMed2003

High expression of p40(tax) and pro-inflammatory cytokines and chemokines in the lungs of human T-lymphotropic virus type 1-related bronchopulmonary disorders.

STUDY OBJECTIVE: Human T-lymphotropic virus type 1 (HTLV-1) is closely associated with the development of certain pulmonary diseases, such as bronchiolitis, although the pathologic mechanism remains unclear. To elucidate the pathogenesis of HTLV-1-associated bronchopulmonary disorders, we analyzed the relationship between expression of p40(tax), a regulatory component of HTLV-1 that stimulates various host genes, and synthesis of pro-inflammatory cytokines and chemokines by cells in BAL fluid (BALF) obtained from HTLV-1-infected patients. DESIGN: Reverse transcription-polymerase chain reaction was used to compare the expression of p40(tax) and pro-inflammatory cytokines and chemokines messenger RNA (mRNA) in BALF of 10 HTLV-1 carriers and 7 healthy subjects. We also studied the correlation between these parameters and the proportion of lymphocytes in BALF. RESULTS: The expression levels of pro-inflammatory cytokines (interferon [IFN]-gamma, interleukin-2) and chemokines (monocyte chemotactic protein-1, macrophage inflammatory protein [MIP]-1alpha, IFN-gamma-inducible protein-10 [IP-10]) were significantly higher in BALF of patients than of healthy subjects. The expression of IFN-gamma and MIP-1alpha mRNA correlated with that of p40(tax). IFN-gamma and IP-10 mRNA expression correlated with the proportion of lymphocytes in BALF. The percentage of lymphocytes in BALF increased with higher expression levels of p40(tax) mRNA, although the correlation was not significant. CONCLUSION: Our results suggested that p40(tax) seems be involved in the development of HTLV-1-associated bronchopulmonary disorders at least in part through the local production of pro-inflammatory cytokines and chemokines.

Adult↗
PubMed2002

Mice lacking bioactive IL-12 can generate protective, antigen-specific cellular responses to mycobacterial infection only if the IL-12 p40 subunit is present.

Recent evidence suggests that absence of the IL-12p40 subunit is more detrimental to the generation of protective responses than is the absence of the p35 subunit. To determine whether this is the case in tuberculosis, both p35 and p40 knockout mice were infected with Mycobacterium tuberculosis. Mice lacking the p40 subunit were highly susceptible to increased bacterial growth, exhibited reduced production of IFN-gamma, and had increased mortality. In contrast, mice lacking the p35 subunit exhibited a moderate ability to control bacterial growth, were able to generate Ag-specific IFN-gamma responses, and survived infection longer. The superior Ag-specific responses of the p35 gene-disrupted mice, when compared with the p40 gene-disrupted mice, suggest that the p40 subunit may act other than as a component of IL-12. A candidate molecule capable of driving the protective responses in the p35 gene-disrupted mice is the novel cytokine IL-23. This cytokine is composed of the IL-12 p40 subunit and a p19 subunit. In support of a role for this cytokine in protective responses to M. tuberculosis, we determined that the p19 subunit is induced in the lungs of infected mice.

Animals↗