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Biomedical subjects

R L Simmons

Publications and source records attributed to R L Simmons.

At least 109 records · Page 6Linked to original sources
PubMed1993

Molecular cloning and expression of inducible nitric oxide synthase from human hepatocytes.

Nitric oxide is a short-lived biologic mediator for diverse cell types. Synthesis of an inducible nitric oxide synthase (NOS) in murine macrophages is stimulated by lipopolysaccharide (LPS) and interferon gamma. In human hepatocytes, NOS activity is induced by treatment with a combination of tumor necrosis factor, interleukin 1, interferon gamma, and LPS. We now report the molecular cloning and expression of an inducible human hepatocyte NOS (hep-NOS) cDNA. hep-NOS has 80% amino acid sequence homology to macrophage NOS (mac-NOS). Like other NOS isoforms, recognition sites for FMN, FAD, and NADPH are present, as well as a consensus calmodulin binding site. NOS activity in human 293 kidney cells transfected with hep-NOS cDNA is diminished by Ca2+ chelation and a calmodulin antagonist, reflecting a Ca2+ dependence not evident for mac-NOS. Northern blot analysis with hep-NOS cDNA reveals a 4.5-kb mRNA in both human hepatocytes and aortic smooth muscle cells following stimulation with LPS and cytokines. Human genomic Southern blots probed with human hep-NOS and human endothelial NOS cDNA clones display different genomic restriction enzyme fragments, suggesting distinct gene products for these NOS isoforms. hep-NOS appears to be an inducible form of NOS that is distinct from mac-NOS as well as brain and endothelial NOS isozymes.

Amino Acid Oxidoreductases↗
PubMed1993

Reactive nitrogen intermediates suppress the primary immunologic response to Listeria.

Reactive nitrogen intermediates (RNI), e.g., nitric oxide derived from a terminal guanido nitrogen atom of L-arginine, exhibit potent antimicrobial activity in vitro. The function of these intermediates in host defenses in vivo, however, is presently unclear. Experiments were undertaken to determine the role of RNI in the resolution of primary listerial infections of the liver. Serum RNI levels were elevated significantly in mice infected with Listeria monocytogenes. Moreover, a marked increase in RNI production was found in cultures of the parenchymal, as well as the nonparenchymal, liver cells obtained from Listeria-infected mice. RNI did not kill Listeria treated directly, however, nor were they a factor in the listericidal activity exhibited by hepatic cells. Rather, the elevated production of RNI during primary infection appeared to promote the replication of Listeria in vivo. Mice administered NG-monomethyl-L-arginine, a competitive inhibitor of RNI production, exhibited a 10- and a 100-fold reduction in the number of Listeria in their lives on days 3 and 7 postinfection, respectively. In vitro, NG-monomethyl-L-arginine stimulated the Ag-specific proliferation of T lymphocytes derived from Listeria-infected mice at concentrations that inhibited RNI production. These latter findings suggest that the elevated production of RNI during primary listerial infections suppresses host defenses by diminishing the proliferation and, consequently, the biologic response of immune cell populations.

Animals↗
PubMed1993

Cytokines, endotoxin, and glucocorticoids regulate the expression of inducible nitric oxide synthase in hepatocytes.

Nitric oxide (NO.) is a short-lived mediator which can be induced in a variety of cell types and produces many physiologic and metabolic changes in target cells. The inducible or high-output NO. synthase (NOS) pathway was first characterized in macrophages activated by lipopolysaccharide (LPS) and interferon gamma (IFN-gamma). Hepatocytes also express an inducible NOS following exposure to the combination of endotoxin (LPS) and tumor necrosis factor (TNF), interleukin 1 (IL-1), and IFN-gamma. In this study, to identify which of these cytokines, if any, was acting to induce the gene expression for hepatocyte NOS, we measured the levels of rat hepatocyte NOS mRNA by Northern blot analysis after stimulation by various combinations of endotoxin and cytokines in vitro. We found the mRNA for hepatocyte NOS to be a single band at approximately 4.5 kilobases which was maximally up-regulated (approximately 70-fold) by the combination of TNF, IL-1, IFN-gamma, and LPS. Abundance of NOS mRNA peaked 6-8 hr after stimulation and then declined by 25% at 24 hr. Unstimulated hepatocytes in vitro showed only a trace mRNA band after prolonged autoradiographic exposure. As single agents, TNF and IL-1 were the most effective inducers of hepatocyte NOS mRNA. Combinations of two or three stimuli revealed strong synergy between TNF, IL-1, and IFN-gamma. The increased mRNA levels correlated with elevated nitrogen oxide release and cGMP levels in the culture supernatants. Dexamethasone and cycloheximide inhibited induction of mRNA for hepatocyte NOS in a dose-dependent fashion. The addition of NG-monomethyl-L-arginine had no effect on mRNA levels but effectively blocked NO. formation. The inducible hepatocyte NOS mRNA was also detected in rat hepatocytes following chronic hepatic inflammation triggered by Corynebacterium parvum injection in vivo. These data demonstrate that the inducible NOS is functional in rat hepatocytes both in vitro and in vivo and that this pathway is under complex control. Endotoxin and inflammatory cytokines act synergistically to up-regulate gene expression for hepatocyte NOS, whereas glucocorticoids down-regulate the mRNA.

Amino Acid Oxidoreductases↗
PubMed1993

Induction of hepatocyte lipopolysaccharide binding protein in models of sepsis and the acute-phase response.

Lipopolysaccharide binding protein (LBP) is a serum glycoprotein that complexes with lipopolysaccharide (LPS) to facilitate macrophage response to endotoxin. To determine the conditions that stimulate LBP production in vivo, we measured the induction of LBP in models of inflammation produced by LPS, Corynebacterium parvum, and turpentine injection. Plasma aspartate aminotransferase and alanine aminotransferase concentrations and hepatocyte fibrinogen synthesis were elevated in all models. Northern blot analysis revealed 17-, 14-, and 20-fold upregulation of hepatocyte LBP mRNA following treatment with LPS, C parvum, and turpentine, respectively. Peritoneal macrophage interleukin 6 and tumor necrosis factor production following endotoxin stimulation was augmented by cultured hepatocyte supernatants, suggesting increased LBP synthesis in these groups. The results show that LBP mRNA is induced during hepatic inflammation and suggest that LBP is an acute-phase protein important in regulating the in vivo response to endotoxin.

Acute-Phase Proteins↗
PubMed1993

Endogenous nitric oxide inhibits the synthesis of cyclooxygenase products and interleukin-6 by rat Kupffer cells.

Macrophage production of nitric oxide (.N = O) leads to considerable alterations of vital metabolic pathways in various target cells. The present study tested whether .N = O synthesis by Kupffer cells (KCs), the resident macrophages of the liver, interferes with the secretory function of these cells. As in other macrophage-type cells, the combination of lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) was a potent stimulus of .N = O synthesis by KC. Treatment with LPS and IFN-gamma also induced significant production of prostaglandin E2 (PGE2), thromboxane B2 (TBX2), tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), and IL-6. Inhibition of .N = O synthesis by KC. Treatment with LPS and IFN-gamma also induced significant production of prostaglandin E2 (PGE2), thromboxane B2 (TBX2), tumor necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1), and IL-6. Inhibition of .N = O synthesis by the L-arginine analogue of NG-monomethyl-L-arginine (NMA) resulted in a further increase of PGE2, TXB2, and IL-6 but not IL-1 and TNF-alpha production, indicating specific inhibitory effects of endogenous .N = O synthesis on the secretory activity of KCs. PGE2 production was most sensitive to the suppressive effect of .N = O and increased 24 h after stimulation with LPS and IFN-gamma from 16.3 +/- 4.9 ng/10(6) KCs without NMA to 94.3 +/- 17.9 ng/10(6) KCs with NMA. This effect of NMA was reversed by a 10-fold increase of the L-arginine concentration. No recovery of PGE2 production was seen when .N = O synthesis was blocked after 24 h. NMA treatment increased cyclooxygenase activity more than threefold, suggesting that .N = O inhibits PGE2 and TXB2 production through diminished PGH2 availability. .N = O synthesis did not significantly affect total protein synthesis or viability of the KCs. These results show that .N = O influences the production of specific inflammatory mediators by KCs.

Animals↗
PubMed1993

Nonheme iron-nitrosyl complex formation in rat hepatocytes: detection by electron paramagnetic resonance spectroscopy.

Isolated rat hepatocytes were examined by EPR spectroscopy after exposure to inflammatory stimuli (interferon-gamma [IFN-gamma], tumor necrosis factor-alpha [TNF-alpha], interleukin-1 beta [IL-1 beta], and lipopolysaccharide [LPS]) in vitro, after in vivo immune activation by Corynebacterium parvum, and after exposure to .N = O and to nitroprusside (nitroferricyanide), an NO-donating nitrovasodilator. Hepatocytes exposed to IFN-gamma, TNF-alpha, IL-1 beta, and LPS demonstrated the appearance of a g = 2.04 axial EPR signal indicative of the formation of nonheme iron-nitrosyl complexes. Concurrent incubation with L-NG-monomethylarginine (L-NMMA), a competitive inhibitor of .N = O synthase, prevented the appearance of the signal. The g = 2.04 signal was localized in the cytosolic fraction of hepatocyte extracts. Hepatocytes freshly isolated from C. parvum-treated rats exhibited a modest g = 2.04 signal, which was increased by a factor of approximately 2.5-fold upon subsequent 24-h culture in media without additional stimuli. This increase was prevented by L-NMMA in the culture medium and also by the presence of rat erythrocytes added to the culture. In the presence of erythrocytes, virtually all of the .N = O produced was oxidized by reaction with intracellular hemoglobin within the erythrocyte, as judged by the relative amounts of nitrite and nitrate detected. These results suggest that in this model system .N = O is sufficiently stable and diffusible to escape from the hepatocyte and diffuse into the erythrocyte without first reacting with oxygen or with intracellular iron at the site of its formation within the hepatocyte. Treatment of hepatocytes with exogenous .N = O or nitroprusside generated an identical g = 2.04 signal of much greater intensity than with cytokines plus LPS. Treatment with nitroprusside also caused the appearance of a signal from pentacyanonitrosylferrate ion, verifying the previously reported metabolism of this nitrovasodilator by reduction and liberation of cyanide ion and .N = O. These results indicate significant differences in intracellular nonheme iron nitrosylation in hepatocytes compared to cytotoxic activated macrophages, which may correlate with the differences in physiological function of .N = O in these two systems.

Animals↗
PubMed1993

Nitric oxide synthase expression is induced in hepatocytes in vivo during hepatic inflammation.

Nitric oxide (NO.) is a short-lived biologic mediator produced by the enzyme NO. synthase (NOS) which exists in constitutive and inducible isoforms. Previously, we have shown that hepatocytes express an inducible NOS in vitro following exposure to the combination of lipopolysaccharide and inflammatory cytokines. The purpose of the present study is to characterize the induction of NOS in vivo in rat hepatocytes during chronic hepatic inflammation triggered by Corynebacterium parvum injection and to correlate NO. synthesis with the timing of liver injury. Using Northern blot hybridization, hepatocyte-inducible NOS mRNA was detected 3 days after C. parvum administration and was not found in normal hepatocytes. Hepatocyte NOS activity was significantly increased 3 to 7 days after C. parvum. Plasma concentrations of nitrite and nitrate (NO2- + NO3-), the stable end products of NO. oxidation, increased from a basal concentration of 21.0 +/- 2.5 to 2439.6 +/- 364.2 microM 3 days after injection. Urinary excretion of NO2- + NO3- also increased in a parallel manner. Plasma liver injury enzymes were elevated three to sixfold in vivo at 3 to 5 days following C. parvum and coincided with the period of maximal NO production. The results show that NO. is produced directly by hepatocytes in vivo during hepatic inflammation and suggest a role for NO. in mediating the hepatic response to inflammatory stimuli.

Amino Acid Oxidoreductases↗
PubMed1993

Hepatocyte injury by activated neutrophils in vitro is mediated by proteases.

OBJECTIVE: This study determined the mechanism used by neutrophils (PMNs) to induce hepatocellular injury. SUMMARY BACKGROUND DATA: Neutrophils have been shown to be potent mediators of cell and tissue injury and have been hypothesized to contribute to the hepatic injury that occurs after trauma and infection. Oxygen radical scavengers protect the liver in vivo from inflammatory injury and it has been suggested that PMNs are the source of these toxic oxygen radicals. The specific mechanism used by PMNs to produce hepatocellular damage, however, has not been determined. METHODS: Neutrophils were cultured in vitro with hepatocytes (HCs) and stimulated with phorbol 12-myristate 13-acetate (PMA) to induce HC injury in the presence of oxygen radical scavengers and protease inhibitors. RESULTS: PMA induced a PMN-mediated HC injury that was dependent on the number of PMNs present and the concentration of PMA. Protease inhibitors reduced the extent of HC injury, while oxygen radical scavengers had no effect. Hydrogen peroxide, directly applied, was able to injure HCs, but only at concentrations greater than those that could be produced by PMA-stimulated PMNs. CONCLUSIONS: PMNs are cytotoxic to cultured HCs, predominantly due to the release of proteolytic enzymes, while HCs appear relatively resistant to oxidative injury. Involvement of neutrophil toxic oxygen radicals in hepatic damage in vivo may require impairment of HC antioxidant defenses or may involve injury to nonparenchymal liver cells with secondary effects on HCs.

Animals↗
PubMed1993

Macrophages produce nitric oxide at allograft sites.

OBJECTIVE: The current study was designed to determine which cytokines produced during an alloimmune response stimulate macrophage nitric oxide (.N = O) production at allograft sites. SUMMARY BACKGROUND DATA: Previous work has demonstrated that rat sponge matrix allograft infiltrating cells produce more .N = O on stimulation with alloantigen than syngeneic graft-infiltrating cells. Addition of NG-monomethyl-L-arginine (NMA), an inhibitor of .N = O synthesis, promotes allospecific cytolytic T-lymphocyte effector function. METHODS: Polyurethane sponges were implanted subcutaneously in recipient Lewis rats and injected with 10 x 10(6) ACl splenocytes. On various days after grafting, graft-infiltrating cells were harvested for in vitro study. Adherent macrophages from the graft infiltrating cell population were obtained by a 2- to 3-hour incubation to plastic dishes with subsequent washing to remove nonadherent cells. RESULTS: Stimulation of unseparated graft-infiltrating cell populations with lipopolysaccharide or interferon-tau resulted in enhanced .N = O synthesis by allograft infiltrating cells compared with syngeneic graft-infiltrating cells, early after grafting. Macrophages recovered from an allograft site spontaneously produce more .N = O than macrophages recovered from syngeneic grafts (p < 0.001). Significantly enhanced levels of .N = O were produced by allograft macrophages compared with syngeneic graft macrophages on stimulation with lipopolysaccharide or interferon-tau (p < or = 0.025). CONCLUSIONS: Nitric oxide appears to be produced in response to the local cytokines secreted by an ongoing rejection reaction. Nitric oxide serves under these circumstances to modulate the alloimmune response.

Animals↗
PubMed1993

Nitric oxide production is inhibited in trauma patients.

Elevated levels of nitrates/nitrites, the stable endproducts of nitric oxide (NO), were recently observed in septic patients. In this setting, NO maintains blood flow by vasodilation and inhibition of platelet aggregation. Trauma patients were found to have low plasma levels of nitrates/nitrites, even when they developed sepsis. The current study substantiated that trauma patients have suppressed production of NO; reductions in plasma nitrate/nitrite levels correlated with low urinary excretion of these endproducts. Nitric oxide production was upregulated in trauma patients with clinical infection compared with trauma patients without infection, but was still significantly suppressed compared with nitric oxide production in normal controls. The inability of trauma patients to produce NO may be an important component of the susceptibility of these patients to infection.

Adolescent↗
PubMed1993

Nitric oxide production by mouse sponge matrix allograft-infiltrating cells. Comparison with the rat species.

We have recently demonstrated in the rat species that sponge matrix allograft infiltrating cells spontaneously produce nitric oxide (.N = 0) and this .N = 0 production precedes the development of CTL. Compared with our experience in the mouse species, the CTL activity recovered from rat sponge grafts is of shorter duration and less intense. Assessment of the spontaneous .N = 0 production by mouse allograft infiltrating cells reveals a more delayed time course of production, paralleling the recovery of CTL activity from the graft. The in vitro spontaneous .N = 0 production by mouse allograft-infiltrating cells was greater than the production by syngeneic graft-infiltrating cells on all days tested. Exposure of allogeneic but not syngeneic graft infiltrating cells to the sensitizing alloantigen in vitro resulted in enhanced .N = 0 synthesis. In contrast, LPS stimulated .N = 0 production by both syngeneic and allogeneic graft cells on all days postgrafting. Culture of day-14 allograft infiltrating cells with alloantigen in the absence of NG-monomethyl-L-arginine (NMA), the competitive inhibitor of .N = 0 synthesis, resulted in elevated supernatant NO2- levels and decreased 3H-TdR uptake and CTL activity compared with cultures carried out in the presence of NMA. The supernatant NO2- levels, as well as the CTL activity and 3H-TdR incorporation of the cultured cells, was dependent on the concentration of NMA present, and these effects could be reversed by excess L-arginine. Thus, the species difference in .N = 0 synthesis (rat > mouse), observed by others, is evident in the sponge allograft model and may explain why CTL activity recovered from rat allografts is of shorter duration and less intense than that from the mouse allografts.

Animals↗
PubMed1993

Evidence for early Th 2 T cell predominance in xenoreactivity.

Two distinct subsets of CD4+ Th lymphocytes have been characterized by their cytokine profiles: Th 1 (TH1) and Th 2 (TH2). While TH1 cells predominate in cell-mediated responses, TH2 cells support the humoral response. We have examined the mRNA cytokine profile of normal mouse lymphocytes in response to alloantigen versus xenoantigen (rat) in MLC, and present evidence to suggest that early in proliferative responses, alloreactivity is dominated primarily by TH1-type lymphocytes, while xenoreactivity is predominantly TH2. Normal mouse lymphocyte-responding cells were cultured in a one-way MLR with either allo or xeno antigen and examined for production of mRNA for cytokines characteristically produced by TH1 (IL-2, IFN-gamma) or TH2 (IL-4, IL-10) cells. Semiquantitative reverse transcription-polymerase chain reaction analysis was performed for mouse IL-2, IL-4, IL-10, and IFN-gamma mRNA. In the mouse anti-rat xeno response, mRNA for TH2 gene products were upregulated, with greater levels of IL-4 and IL-10 at 24 and 48 hr when compared with controls. In contrast, upregulation of mRNA for TH1 gene products occurred in the mouse anti-mouse allo response, with higher levels of IL-2 and IFN-gamma at 24 and 48 hr. In the anti-xeno response, upregulation of all 4 cytokines occurred by day 4 and peak levels of mRNA for all cytokines examined were 2-3 times that seen for the peak anti-allogeneic response. These data suggest that early xenorecognition may differ from allorecognition by differential activation of the TH2 subset. A better understanding of the balance between Th subset function and cytokine profile in allo and xeno reactivity may allow a more targeted and specific approach to control the early events in xenograft rejection.

Animals↗
PubMed1993

A dual mechanism of immunosuppression by FK-506. Differential suppression of IL-4 and IL-10 levels in T helper 2 cells.

FK-506 is known to suppress the transcription of several genes encoding cytokines (e.g., IL-2, IFN-gamma) thought to play an important role in the allograft response. This general inhibition of cytokine gene transcription and protein production was previously thought to be the main mechanism by which FK-506 suppressed the immune response. We have studied the pattern of cytokine suppression caused by FK-506 in differentiated murine Th 2 cell lines. Supernatants from Th2 cells treated with FK-506 showed marked suppression of IL-4 but only moderate suppression of IL-10 levels. To determine whether this differential effect on IL-4 and IL-10 could also be seen at the mRNA level, total cellular RNA was isolated from cells treated with (1) media, (2) Con A (2 micrograms/ml), (3) FK-506 (50 ng/ml), or (4) Con A + FK-506. Reverse transcription-polymerase chain reaction and northern blot analysis were used to measure IL-4 and IL-10 mRNA. Similar to results at the protein level, FK-506 suppressed steady state levels of IL-4 mRNA markedly but had a lesser effect on steady state levels of IL-10 mRNA. Furthermore, FK-506 completely abrogated Con A-induced upregulation of IL-4 mRNA, but only slightly suppressed Con A-induced upregulation of IL-10 mRNA. IL-10 (cytokine synthesis inhibitory factor) is a cytokine with immunosuppressive properties that itself inhibits the production of IL-2 and IFN-gamma murine helper cells. IL-10 also downregulates MHC II expression and antigen presentation by monocytes. Therefore, the ability of FK-506 to differentially suppress the mRNA levels of immunostimulatory cytokines such as IL-2, IL-4, and IFN-gamma more than the mRNA levels of the immunosuppressive cytokine IL-10 suggests that the effective immunosuppression seen in vivo with FK-506 may be a combination of these 2 effects.

Animals↗
PubMed1993

CNS aspergillosis in organ transplantation: a clinicopathological study.

The clinical characteristics and neuropathological findings of 22 organ transplant recipients with CNS aspergillosis were reviewed. Thirteen patients had liver, six kidney, two heart and one had cluster transplants. The most frequent neurological symptoms were alteration of mental status (86%), seizures (41%) and focal neurological deficits (32%). Meningeal signs were less common (19%). Aspergillus spp invasion of the blood vessels with subsequent ischaemic or haemorrhagic infarcts, and solitary or multiple abscesses were the predominant neuropathological findings. The lungs were the probable portal of entry; however, isolated CNS aspergillosis was seen in two patients. Antemortem diagnosis of the infection was made in half of the patients. Concomitant diabetes mellitus was noted in 59% of the patients and bacterial or other severe infections in 86%. No specific clinical or pathological pattern could be identified among patients with different types of organ transplants. In addition CNS aspergillosis was preceded by organ rejection and the need for intense immunosuppression and retransplantation in the majority of the patients.

Adolescent↗
PubMed1993

Loin pain hematuria syndrome.

LPHS is a disorder of obscure etiology and inconsistent pathology whose most prominent clinical feature is severe flank pain. Were it not for the hematuria which nearly always accompanies the pain, there would be no specific objective correlate of the syndrome. In this sense, it is similar to a number of chronic conditions which have inspired heated controversy about their very existence as discrete diseases. As the foregoing discussion of pathogenesis, pathology and diagnosis illustrates, with respect to two important characteristics of a 'prototypical' disease--specificity and mechanism--LPHS falls far short. This, coupled with a rather unimpressive 'visible' concomitant of the symptoms (hematuria), has inspired skepticism and even suspicion in some physicians confronted with the demands for analgesia by these patients. On the part of physicians who have been involved in the care of these patients over time, however, there is no doubt that they suffer from a bona fide illness, if not a disease. The severity of the illness is evinced by the rather extreme measures that have been taken in its treatment; e.g., surgical denervation of the kidney, nephrectomy, autotransplantation. Only the last of these appears to offer the hope of enduring pain relief while preserving renal function, but the risk of pain recurrence in the autograft may limit the usefulness of this procedure. Accordingly, narcotic analgesics may need to be the treatment of first and last resort. Development of specific treatment will depend upon elucidating the pathogenesis of the disorder. The available data suggest further investigation of the role of vasoactive mediators, and the coagulation and immune systems.

Diagnosis, Differential↗
PubMed1993

Cytokine induction of interferon regulatory factor-1 in hepatocytes.

BACKGROUND: Interferon regulatory factor-1 (IRF-1) is a transcriptional factor originally cloned from fibroblasts that activates interferons and certain interferon-responsive genes. Because IRF-1 is an "early-immediate" nuclear protein, it can function acutely after trauma or septic stimuli. We have identified IRF-1 expression in hepatocytes in vivo in sepsis. The purpose of this study was to characterize the cytokine signals that up-regulate IRF-1 messenger RNA (mRNA) in cultured hepatocytes. METHODS: Rat hepatocytes were isolated by in situ collagenase perfusion and stimulated in vitro with cytokines. IRF-1 mRNA levels were determined by Northern blot hybridization with a DNA probe for hepatocyte IRF-1 generated with reverse transcription polymerase chain reaction with custom-designed oligonucleotide primers based on the known sequence for T-cell IRF-1. RESULTS: Northern blot of hepatocyte RNA showed a single IRF-1 mRNA band at approximately 2.4 Kb. The mRNA levels were markedly up-regulated (vs control hepatocytes) 2 hours after in vitro stimulation with the cytokines interferon-gamma (17-fold), tumor necrosis factor-alpha (3-fold), and interleukin-1 beta (2-fold). Lipopolysaccharide had no direct effect. CONCLUSIONS: The results showed that IRF-1 is up-regulated in hepatocytes primarily in response to interferon-gamma and to a lesser extent after tumor necrosis factor-alpha or interleukin-1 beta stimulation. This suggests that IRF-1 plays a role in regulating liver gene expression in sepsis; however, the specific genes controlled by IRF-1 remain to be determined.

Animals↗