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PubMed1996

Inducible translational regulation of the NF-IL6 transcription factor by respiratory syncytial virus infection in pulmonary epithelial cells.

Respiratory syncytial virus (RSV), the most common etiologic agent of epidemic pediatric respiratory disease, infects and replicates in the human airway epithelium, resulting in the induction of cellular gene products essential for immune and inflammatory responses. We describe the effect of RSV infection on nuclear factor-IL6 (NF-IL6) expression, a human basic domain-leucine zipper-containing transcription factor that alone in combination with other inducible transcription factors regulates the expression of cytokine and adhesion molecule genes. RSV-infected human type II pulmonary alveolar epithelial cells (A549) synthesize a single 45.7-kDa isoform of NF-IL6 rapidly and in a time-dependent manner. NF-IL6 is first detectable after 3 h of infection and continues to accumulate until 48 h (until the cells lose viability). NF-IL6 production could not be induced by UV-inactivated virus, demonstrating the requirement of viral replication for NF-IL6 synthesis. Immunoprecipitation after [35S]methionine metabolic labeling was done to investigate the mechanism for NF-IL6 production. There was robust NF-IL6 protein synthesis within RSV-infected (24 h) cells. Protein synthesis occurred without detectable changes in the abundance or size of the single 1.8-kb NF-IL6 mRNA. RNase protection assay of transfected chloramphenicol acetyltransferase reporter genes driven by either wild-type or mutated NF-IL6 binding sites show a virus-induced increase in NF-IL6-dependent transcription. These studies have demonstrated a novel inducible mechanism for translational control of NF-IL6 synthesis and identify this transcription factor as a potential effector of the host response to RSV infection.

Base Sequence↗
PubMed1994

Fos and Jun repress transcription activation by NF-IL6 through association at the basic zipper region.

NF-IL6 and AP-1 family transcription factors are coordinately induced by interleukin-6 (IL-6) in a cell-type-specific manner, suggesting that they mediate IL-6 signals in the nucleus. We show that the basic leucine zipper (bZIP) region of NF-IL6 mediates a direct association with the bZIP regions of Fos and Jun in vitro. This interaction does not depend on the presence of their cognate recognition DNA elements or the posttranslational modification of either partner. NF-IL6 homodimers can bind to both NF-IL6 and AP-1 sites, whereas Fos and Jun cannot bind to most NF-IL6 sites. Cross-family association with Fos or with Jun alters the DNA binding specificity of NF-IL6 and reduced its binding to NF-IL6 sites. NF-IL6 isoforms that differ in the site of translation initiation have distinct transcriptional activities. Activation of a reporter gene linked to the NF-IL6 site by NF-IL6 is repressed by Fos and by Jun in transient transfection assays. Thus, association with AP-1 results in repression of transcription activation by NF-IL6. The repression is NF-IL6 site dependent and may have a role in determining the promoter and cell type specificity in IL-6 signaling.

Base Sequence↗
PubMed1989

Adult human vascular endothelial cells express the IL6 gene differentially in response to LPS or IL1.

We investigated the regulation of IL6 biological activity, de novo synthesis, and mRNA levels in adult vascular endothelial cells (EC) by bacterial endotoxin or inflammatory cytokines. Cells incubated without stimulus released scant IL6 activity. IFN gamma, IL2, or PDGF did not augment IL6 release from EC. LPS, lipid A, and TNF increased IL6 release modestly (5 to 20-fold), while recombinant IL1s (rIL1s) stimulated this process 100 to 400-fold. Differential release of IL6 from EC treated with LPS or rIL1 continued for at least 144 hr. Exposure to LPS or rIL1 caused EC to synthesize IL6 de novo. EC secreted the newly synthesized IL6 into the supernatant, rather than retaining it within or bound to cells. EC accumulated IL6 mRNA after 3 hr of exposure to rIL1. However, we could only detect IL6 message in cells incubated with LPS under "superinduction" conditions with cycloheximide, consistent with lower levels of IL6 biological activity in response to LPS compared to IL1 stimulation. We propose that local production of IL6 by vascular EC, which comprise the barrier between tissues and the blood, may influence regional immune and inflammatory responses.

Antigen-Antibody Reactions↗
PubMed1998

Pediatric acute myelogenous leukemia cells express IL-6 receptors and are sensitive to a recombinant IL6-Pseudomonas exotoxin.

We have studied IL-6 receptor (IL-6R) expression on AML cells from 15 pediatric patients by immunocytochemistry/flow cytometry, reverse-transcription polymerase chain reaction, and Scatchard analysis. High-affinity IL-6R were detected on leukemic cells from 12 (80%) patients. Binding sites per cell ranged from 140 to 3580 (median 920; mean 1240), with dissociation constants of 0.26 to 0.71 nM. We therefore assessed the in vitro sensitivity of IL-6R+ AML cells to treatment with a recombinant IL6-Pseudomonas exotoxin fusion protein (IL6-PE4E), using the XTT cytotoxicity assay. Leukemic cells from eight patients had ID50 values (concentration of IL6-PE4E producing a 50% decrease in cell viability) of <1000 ng/ml (median, 87 ng/ml; mean, 262 ng/ml). Sensitivity to IL6-PE4E correlated significantly with receptor number. Normal bone marrow mononuclear cells had undetectable IL6-R expression (<20 receptors/cell) and were relatively resistant to IL6-PE4E. To test the efficacy of IL6-PE4E for ex vivo purging in an autologous stem cell transplantation setting, we incubated primary IL-6R+ AML cells with 10(3) ng/ml IL6-PE4E for 24 h, followed by inoculation into SCID mice. Mice receiving treated cells showed no leukemic engraftment, while all mice receiving untreated or control-treated cells developed leukemia with a median presymptomatic interval of 55 days. In recipients of IL6-PE4E treated cells, no evidence of occult leukemia was detected by PCR analysis of blood and bone marrow cells at 185 days postinoculation. These data suggest that IL-6R are expressed on leukemic cells from a substantial percentage of pediatric AML patients. Furthermore, leukemic cells expressing high numbers of IL6-R may be sensitive to IL6-PE4E in an ex vivo purging protocol.

ADP Ribose Transferases↗
PubMed1997

Expression of exogenous NF-IL6 induces apoptosis in Sp2/0-Ag14 myeloma cells.

NF-IL6 (or C/EBP beta) is a multifunctional transcription factor of the C/EBP family. To study the effects of exogenous expression of NF-IL6 on the growth of cells of hematopoietic tumors, we infected SP2/0-Ag14 myeloma cells with pLXSN recombinant retrovirus harboring the NF-IL6 cDNA. We found that the transfected cells revealed changes typical of the apoptosis and finally died. The expression of NF-IL6 protein was shown by a "supershift" assay in the NF-IL6-transfected cells. In controls, where cells were infected by the retroviral vector with a mutant NF-IL6 coding region as well as the vector without insert, no sign for expression of NF-IL6 and apoptosis was observed. Therefore, our work shows that the apoptosis of this myeloma cell line was induced by the exogenous NF-IL6 expression. This is significantly different from the apparent effects of NF-IL6 in leukemia cells and in fibroblasts. These facts indicate that NF-IL6 exerts different functions in different cell types. We discuss possible mechanisms for the NF-IL6-induced apoptosis.

Animals↗
PubMed2003

Association of a functional 17beta-estradiol sensitive IL6-174G/C promoter polymorphism with early-onset type 1 diabetes in females.

The type 1 diabetes mellitus (T1DM) candidate gene SNP IL6-174G/C was genotyped in 253 Danish T1DM families (1129 individuals). TDT analysis demonstrated linkage in the presence of association between the IL6-174C allele and T1DM in the 416 T1DM offspring, P(tdt)=0.04. Gender conditioned TDT analyses revealed that linkage and association with T1DM were present in females exclusively; P(tdt)=6.5 x 10(-4) and P(tdt)=2.4 x 10(-4), respectively. Random transmission of the IL6-174C/G alleles was found in T1DM males, non-T1DM males and non-T1DM females; all P(tdt)>/=0.37. Heterogeneity analyses (T1DM versus non-T1DM females) excluded preferential meiotic segregation in females, P=4.6 x 10(-3), and demonstrated differences in the transmission patterns between female and male T1DM offspring, P=5.1 x 10(-3). The IL6-174 CC genotype was associated with younger age at onset of T1DM in females (P=0.002). The impact of 17beta-estradiol (E(2)) on the IL6-174G/C variants was investigated by reporter studies. The PMA stimulated activity of the T1DM risk IL6-174C variant exceeded that of the T1DM protective IL6-174G variant by approximately 70% in the absence of E(2) (P(c)=0.004), but not with E(2) present (P(c)=0.12). The PMA stimulated activity of the IL6-174G variant was repressed without E(2) present, but was derepressed by addition of E(2), P(c)=0.024. In contrast, the PMA stimulated IL6-174C activity was unaffected by E(2) as were the constitutive activities of the IL6-174G/C variants. In conclusion, higher IL6 promoter activity may confer risk to T1DM in very young females. This excess risk is negated with increasing age, possibly by the increasing E(2) levels in puberty.

Age of Onset↗
PubMed1992

NF-IL6, a member of the C/EBP family, regulates E1A-responsive promoters in the absence of E1A.

A cDNA encoding NF-IL6, an interleukin-6 (IL-6)-regulated human nuclear factor of the C/EBP family, is demonstrated to complement the transactivation function of E1A. The endogenous NF-IL6 level varies according to cell type and correlates positively with an IL-6-regulated cellular E1A-substituting activity that was described recently (J.M. Spergel and S. Chen-Kiang, Proc. Natl. Acad. Sci. USA 88:6472-6476, 1991). When expressed by transfection in cells which contain low levels of NF-IL6 and are incapable of complementing the function of E1A proteins, NF-IL6 also transactivates the E1A-responsive E2ae and E1B promoters, to the same magnitude as E1A. Activation by NF-IL6 is concentration dependent and sequence specific: mutational studies of the E2ae promoter suggest that the promoter-proximal NF-IL6 recognition site functions as a dominant negative regulatory site whereas the promoter-distal NF-IL6 recognition site is positively regulated at low NF-IL6 concentrations and negatively regulated when the NF-IL6 level is high. Consistent with these functions, NF-IL6 alone is sufficient to complement an E1A deletion mutant dl312 in viral infection, when expressed at appropriate concentrations. These results identify NF-IL6 as a sequence-specific cellular nuclear factor which regulates E1A-responsive genes in the absence of E1A.

Adenovirus Early Proteins↗
PubMed1992

[Synergism between transcription factors NF-IL6 and NF-kappa B in IL-6 gene regulation].

NF-IL6 and NF-kappa B are nuclear proteins supposed to play an important role in the regulation of acute-phase protein synthesis and inflammatory response against infection and tissue injury as a host defence mechanism. In addition the promoter region of the interleukin-6 (IL-6) gene has a NF-kappa B binding motif as well as a NF-IL6 binding site. Considering of these facts, we come to investigate that there may be a synergistic effect between NF-IL6 and NF-kappa B in the regulation of IL-6 gene expression. In order to study it, some combinations of expression vectors NF-IL6 cDNA, NF-kappa B (p50/p65) cDNA and reporter plasmid K18-CAT which contains human IL-6 promoter linked to the chloramphenicol acetyltransferase (CAT) gene, were transfected into Jurkat cells and the CAT activities were examined. Co-transfection of NF-IL6 and NF-kappa B (p50/p65) cDNA revealed a dramatic increase of acetylated [14C] chloramphenicol, and its CAT activity reached to 40%. Then, co-transfection of NF-IL6 and NF-kappa B subunit p65 alone showed a high level of CAT activity, too. When 5' deletion mutant reporter plasmid K9-CAT lacking the NF-IL6 binding site was used, co-transfection of NF-IL6 and NF-kappa B (p50/p65) showed low level of CAT activity. These results indicate that there is a synergistic effect between NF-IL6 and NF-kappa B (p50/p65) in IL-6 gene regulation. Among two subunits of NF-kappa B (p50/p65), p65 seems to play an important role rather than p50 does in synergism between NF-IL6 and NF-kappa B. Besides, this synergistic function comes to work only when NF-IL6 binds to its binding site of IL-6 promoter region.

Binding Sites↗
PubMed1989

Recombinant interleukin (IL) 2-induced human B cell differentiation is mediated by autocrine IL6.

The molecular mechanism of the interleukin (IL) 2-induced differentiation of human B cells has been investigated. The experimental results show that Staphylococcus aureus Cowan strain I (SAC) activation alone induces IL6 secretion from B cells. When B cells were activated by SAC, there was an increased transcription of the IL6 mRNA. It reached the peak level by 6 h and rapidly decreased to an undetectable level within 24 h. The IL6 concentration in the culture supernatants reached the peak at 24-48 h and decreased slightly in the following culture periods. Since IL 2 alone could induce IgG secretion, whether exogenous IL6 was added or not, and IL2 did not increase autocrine IL6 synthesis, it appears that IL2 induces the IL6 responsiveness of SAC-activated B cells to differentiate in the later stage of the culture. The addition of polyclonal anti-IL6 antibody inhibited IgG secretion. The antibody still efficiently blocked IgG secretion up to day 5, indicating an important role of autocrine IL6 in the IL2-driven B cell differentiation. However, the saturation dose of anti-IL6 antibody inhibited 50%-70% of IgG secretion, suggesting that IL2-induced B cell differentiation appears to be mediated by other factors besides IL6.

B-Lymphocytes↗
PubMed1993

Transforming growth factor beta-1 (TGF-beta 1) potentiates IL1 alpha-induced IL6 mRNA and cytokine protein production in a human astrocytoma cell line.

We analyzed the response of human astrocytoma cell line U373-MG to various cytokines by measuring the production of interleukin-6 (IL6) mRNA and cytokine protein. Interferon gamma (IFN gamma), transforming growth factor beta 1 (TGF-beta 1), granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte-colony-stimulating factor (G-CSF) did not induce IL6 mRNA production; however, IL6 mRNA expression and protein production was strongly induced by IL1 alpha and to a lesser extent by IFN alpha. The IL6 mRNA expression induced by IL1 alpha was potentiated by TGF-beta 1 and IFN alpha and slightly decreased by IFN gamma. The potentiation of cytokine mRNA accumulation by TGF-beta 1 was both time- and concentration-dependent. Induction of IL6 mRNA by IL1 alpha was optimally potentiated either if U373-MG cells were pretreated with TGF-beta 1 or if TGF-beta 1 was added within 30 min after stimulation with IL1 alpha. The potentiation of IL6 mRNA by TGF-beta 1 required de novo synthesis of an intermediate protein since treatment with cycloheximide abrogated the amount of mRNA enhanced by TGF-beta 1 without affecting IL1 alpha-driven mRNA production. Nuclear run-on analyses demonstrated increased transcriptional activity of the IL6 gene when stimulated with IL1 alpha in the presence of TGF-beta 1. However, actinomycin-D pulse chase experiments showed that TGF-beta 1 did not increase the stability of IL6 mRNA. Thus, in concert, the results demonstrate that TGF-beta 1 potentiates IL6 production in astrocytoma cells by promoting the transcriptional activity of the IL6 gene and requires coexpression of new proteins. Since cytokines can provide potent mitogenic signals to tumor cells, the results presented here further suggest that the antitumor effect of combination cytokine therapy might partly depend on heterotypic interactions between tumor cells and cytokines.

Astrocytoma↗
PubMed1992

Regulation of expression of the interleukin 6 gene: structure and function of the transcription factor NF-IL6.

The interleukin 6 (IL-6) promoter is rapidly and transiently activated by other cytokines, including IL-1 and tumour necrosis factor (TNF), as well as by phorbol esters and cyclic AMP agonists. Studies using promoter mutants suggested that an IL-1-responsive element mapped within the -180 to -123 region of the IL-6 promoter. A nuclear factor (NF-IL6) that recognized a unique sequence containing an inverted repeat, ACATTGCACAATCT, was identified within the region. Direct cloning of the human NF-IL6 revealed its similarity to C/EBP, a liver- and adipose tissue-specific transcription factor. C/EBP and NF-IL6 recognize the same nucleotide sequence, but exhibit distinct patterns of expression. NF-IL6 is expressed at a low level in normal tissues, but is rapidly and drastically induced by bacterial lipopolysaccharide (LPS) or inflammatory cytokines such as IL-1, TNF and IL-6. Recently, NF-IL6 has been shown to be identical to IL-6DBP, the DNA-binding protein which is responsible for IL-6-mediated induction of several acute-phase proteins. Evidence that NF-IL6 DNA-binding activity is increased after IL-6 stimulation without increased NF-IL6 protein synthesis demonstrates the importance of post-translational modification. There are some results indicating that phosphorylation is involved in transcriptional and binding activities of NF-IL6. Taken together, these findings indicate that NF-IL6 may be an important transcription factor on the signal transduction pathways of IL-1 and IL-6.

Acute-Phase Proteins↗
PubMed1996

Regulation of HIV-1 gene expression by NF-IL6.

Previous studies have shown that in human T-cells (Jurkat) and hepatoma cells (HepG2), exogenous NF-IL6 can activate HIV-1 gene expression even in the absence of its consensus binding elements in the viral long terminal repeat (LTR). To identify the LTR elements that mediate this response, we have analysed constructs containing mutated and deleted LTR sequences. We have also examined heterologous plasmids to evaluate a potential requirement for the natural LTR sequences in producing HIV-1 gene activation by NF-IL6. As observed for Jurkat and HepG2 cells, we find that in the absence of NF-IL6 binding elements, NF-IL6 can elicit LTR-mediated gene expression in cotransient expression assays performed in monocytic (U937) cells. However, we detect distinct modes of regulation depending on cell type. In U937 cells, the basal LTR sequences retain a significant fraction (42%) of NF-IL6 responsiveness in the absence of upstream regulatory elements in the LTR while these elements are required for maximal response. In HepG2 cells, NF-IL6 elicits a relatively low level of gene activation from the basal LTR elements; response to NF-IL6 is restored with either the Sp1 binding sequences or the other upstream regulatory elements in the LTR. In addition, even though NF-IL6 induces a relatively low gene activity from the basal LTR sequences analysed in HepG2 cells, study of a heterologous construct indicates that these sequences are required for the responsiveness of Sp1 elements to NF-IL6 in this cellular background.

Binding Sites↗
PubMed1995

Targeted disruption of the NF-IL6 gene discloses its essential role in bacteria killing and tumor cytotoxicity by macrophages.

To investigate the role of NF-IL6 in vivo, we have generated NF-IL6 (-/-) mice by gene targeting. NF-IL6 (-/-) mice were highly susceptible to infection by Listeria monocytogenes. Electron microscopic observation revealed the escape of a larger number of pathogens from the phagosome to the cytoplasm in activated macrophages from NF-IL6 (-/-) mice. Furthermore, the tumor cytotoxicity of macrophages from NF-IL6 (-/-) mice was severely impaired. However, cytokines involved in macrophage activation, such as TNF and IFN gamma, were induced normally in NF-IL6 (-/-) mice. Nitric oxide (NO) formation was induced to a similar extent in macrophages from both wild-type and NF-IL6 (-/-) mice. These results demonstrate the crucial role of NF-IL6 in macrophage bactericidal and tumoricidal activities as well as the existence of a NO-independent mechanism of these activities. We also demonstrate that NF-IL6 is essential for the induction of G-CSF in macrophages and fibroblasts.

Animals↗
PubMed1994

NF-IL6 and AP-1 cooperatively modulate the activation of the TSG-6 gene by tumor necrosis factor alpha and interleukin-1.

Tumor necrosis factor alpha (TNF-alpha) and interleukin-1 (IL-1) activate transcription of the TSG-6 gene in normal human fibroblasts through a promoter region (-165 to -58) that encompasses an AP-1 and a NF-IL6 site. We show by deletion analysis and substitution mutagenesis that both sites are necessary for activation by TNF-alpha. Activation by IL-1 requires the NF-IL6 site and is enhanced by the AP-1 site. These results suggest that the NF-IL6 and AP-1 family transcription factors functionally cooperate to mediate TNF-alpha and IL-1 signals. Consistent with this possibility, IL-1 and TNF-alpha markedly increase the binding of Fos and Jun to the AP-1 site, and NF-IL6 activates the native TSG-6 promoter. Activation by NF-IL6 requires an intact NF-IL6 site and is modulated by the ratio of activator to inhibitor NF-IL6 isoforms that are translated from different in-frame AUGs. However, the inhibitor isoform can also bind to the AP-1 site and repress AP-1 site-mediated transcription. The finding that the inhibitor isoform antagonizes activation of the native TSG-6 promoter by IL-1 and TNF-alpha suggests that NF-IL6 has a physiologic role in these cytokine responses. Thus, the functionally distinct NF-IL6 isoforms cooperate with Fos and Jun to positively and negatively regulate the native TSG-6 promoter by TNF-alpha and IL-1.

Base Sequence↗
PubMed1999

A novel LPS-inducible C-type lectin is a transcriptional target of NF-IL6 in macrophages.

C-type lectins serve multiple functions through recognizing carbohydrate chains. Here we report a novel C-type lectin, macrophage-inducible C-type lectin (Mincle), as a downstream target of NF-IL6 in macrophages. NF-IL6 belongs to the CCAAT/enhancer binding protein (C/EBP) of transcription factors and plays a crucial role in activated macrophages. However, what particular genes are regulated by NF-IL6 has been poorly defined in macrophages. Identification of downstream targets is required to elucidate the function of NF-IL6 in more detail. To identify downstream genes of NF-IL6, we screened a subtraction library constructed from wild-type and NF-IL6-deficient peritoneal macrophages and isolated Mincle that exhibits the highest homology to the members of group II C-type lectins. Mincle mRNA expression was strongly induced in response to several inflammatory stimuli, such as LPS, TNF-alpha, IL-6, and IFN-gamma in wild-type macrophages. In contrast, NF-IL6-deficient macrophages displayed a much lower level of Mincle mRNA induction following treatment with these inflammatory reagents. The mouse Mincle proximal promoter region contains an indispensable NF-IL6 binding element, demonstrating that Mincle is a direct target of NF-IL6. The Mincle gene locus was mapped at 0.6 centiMorgans proximal to CD4 on mouse chromosome 6.

Animals↗
PubMed1990

A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family.

NF-IL6 is a nuclear factor that specifically binds to an IL1-responsive element in the IL-6 gene. In this study the gene encoding NF-IL6 has been cloned by direct screening of a lambda gt11 library using NF-IL6 binding sequence as a ligand. The full-length cDNA encoded a 345 amino acid protein with a potential leucine zipper structure and revealed a high degree of homology to a liver-specific transcriptional factor, C/EBP, at the C-terminal portion. The bacterial fusion protein bound to the CCAAT homology as well as the viral enhancer core sequences as in the case of C/EBP. Recombinant NF-IL6 activated the human IL-6 promoter in a sequence-specific manner. Southern blot analysis demonstrated the high-degree conservation of the NF-IL6 gene through evolution and the existence of several other related genes sharing the DNA-binding domain. NF-IL6 mRNA was normally not expressed, but induced by the stimulation with either LPS, IL-1 or IL-6. Interestingly, NF-IL6 was shown to bind to the regulatory regions for various acute-phase protein genes and several other cytokine genes such as TNF, IL-8 and G-CSF, implying that NF-IL6 has a role in regulation not only for the IL-6 gene but also for several other genes involved in acute-phase reaction, inflammation and hemopoiesis.

Acute-Phase Reaction↗
PubMed1991

Constitutive release of IL6 by human papillomavirus type 16 (HPV16)-harboring keratinocytes: a mechanism augmenting the NK-cell-mediated lysis of HPV-bearing neoplastic cells.

In the present study we demonstrate that the cultured human keratinocyte cell line (SK-v cells) harboring and expressing integrated human papillomavirus type 16 (HPV16) DNA sequences constitutively releases IL6, which is known as a pleiotropic immunoregulatory cytokine of potential antitumor properties. The presence of IL6 activity in SK-v cell-conditioned media (SK-v CM) was demonstrated by tritiated thymidine incorporation into IL6-dependent B9 murine plasmacytoma cells. The effect on B9 cells was specific since it could be inhibited by anti-IL6 neutralizing antibodies but not by a normal control serum. IL6 did not affect SK-v cell growth; however, it significantly augmented NK cell activity of human peripheral blood lymphocytes against both K562 erytholeukemic and SK-v cells as assessed by 51Cr release assay. SK-v CM displayed NK cell-augmenting activity that copurified with IL6 activity in both size exclusion and anion-exchange HPLC. Furthermore, SK-v cell-derived NK cell stimulatory activity could be neutralized with anti-IL6 antibodies. These results suggest that HPV-harboring neoplastic cells can release IL6 which may indirectly mediate tumor death by augmentation of NK cell activity.

Cytotoxicity, Immunologic↗
PubMed1992

Effects of IL6 on B cells in mucosal immune response and inflammation.

Freshly isolated surface IgA+ (sIgA+) B cells from human gut-associated lymphoreticular tissues (GALT), e.g. the appendix, express high levels of IL6 receptor (IL6R) and respond to IL6 with significant increases in the number of IgA-secreting cells. On the other hand, neither sIgM+ nor sIgG+ B cells from appendix express IL6R. When the effect of IL6 on IgA subclass antibody synthesis was examined, the numbers of both IgA1- and IgA2-producing cells were increased upon incubation of GALT B cells with IL6; however, 60-70% of IgA-secreting cells were IgA2 subclass. Aberrant local production of IL6 can contribute to increased B-cell responses that occur in mucosal inflammation such as gingiva of patients with adult periodontitis (AP). When gingival mononuclear cells (GMC) isolated from AP patients were cultured without any stimulus, GMC spontaneously produced biologically active IL6 which induced peripheral blood mononuclear cells (PBMC) from the same patients to become IgG- and IgA-producing cells. Further, mRNA extracted from GMC possessed high message for IL6. When the expression of IL6R was compared between GMC and PBMC isolated from AP patients, IL6R-bearing cells were only seen in the former population. Thus, a high production of IL6, which have the ability to regulate later stages of IL6R+ B-cell development and to induce them to become Ig-secreting plasma cells and to support plasmacytoma growth, are important immunopathological elements for the induction of the increased B-cell response region in inflamed mucosal tissues.

Appendix↗