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The effects of tumor necrosis factor on the production of interleukin-1 by macrophages
Abstract
We investigated the effect of tumor necrosis factor (TNF) on interleukin-1 (IL-1) production by mouse macrophages. At high doses of TNF, macrophages produced no IL-1 (as judged in the LAF assay) even when exposed to bacterial lipopolysaccharide (LPS), an excellent inducer of IL-1 production. In lower (picogram/ml) doses, TNF caused macrophages to make factors which showed modest activity in the LAF assay and that activity could be blocked by antibody to IL-1. TNF induces in low doses also the production of a factor(s) which synergizes with IL-1 in the LAF assay.
... Tumour necrosis factor (TNF)-a is an important cytokine implicated in the pathogenesis of juvenile idiopathic arthritis (JIA), and can induce expression of other proinflammatory cytokines such as interleukin (IL)-1b, IL-6 and IL-8, leading to an overall protracted inflammatory response [1][2][3][4]. In the normal physiological state, proinflammatory cytokines, including TNF-a, are maintained in equilibrium with anti-inflammatory cytokines, such as IL-10. ...
... TNF-a, IL-6 and IL-8 all contribute to inflammatory pathways that are probably active in JIA patients. TNF-a is derived by macrophages and lymphoid cells that induce expression of other cytokines, including IL-6 and IL-8, thereby initiating an inflammatory response [3,4]. TNF-a and IL-6 have multiple effects on vascular endothelial cells, leucocytes and bone marrow. ...
OBJECTIVE:
To prospectively evaluate cytokine levels and disease activity in juvenile idiopathic arthritis (JIA) patients treated with and without tumor necrosis factor (TNF)-α inhibitors.
METHODS:
TNF-α inhibitor-naïve JIA subjects were followed prospectively over 6 months. Cytokine levels of TNF-α, interleukin (IL)-1β, IL-6, IL-8, IL-10 and IL-17 were measured at baseline for JIA subjects and healthy controls (HCs). Cytokine levels were then measured at 4 time points after initiation of TNF-α inhibition for anti-TNF-α treated (anti-TNF) JIA subjects, and at 2 subsequent time points for other JIA (non-TNF) subjects. JIA disease activity by Childhood Health Assessment Questionnaire (CHAQ) disability index/pain score and physician joint count/global assessment was recorded.
RESULTS:
Sixteen anti-TNF, 31 non-TNF, and 16 HCs were analyzed. Among JIA subjects, those with higher baseline disease activity (subsequent anti-TNFs) had higher baseline TNF-α, IL-6 and IL-8 than those with lower disease activity (non-TNFs) (p <0.05). TNF-α and IL-10 increased, and IL-6 and IL-8 no longer remained significantly higher after TNF-α inhibitor initiation in anti-TNF subjects. Subgroup analysis of etanercept versus adalimumab treated subjects showed that TNF-α and IL-17 increased significantly in etanercept but not adalimumab treated subjects, despite clinical improvement in both groups of subjects.
CONCLUSION:
JIA subjects with increased disease activity at baseline had higher serum pro-inflammatory cytokines. TNF-α inhibition resulted in suppression of IL-6 and IL-8 in parallel with clinical improvement in all anti-TNF treated subjects, but also was associated with elevated TNF-α and IL-17 in etanercept treated subjects.
... TNFα and lymphokine TNFβ have both demonstrated direct and indirect effects on hematopoiesis. Indirectly, TNF can influence hematopoiesis through the induction of cytokine production by a number of cell types [190][191][192][193][194][195][196]. Thus, TNF may indirectly augment hematopoiesis. ...
... The further addition of G-CSF, M-CSF or GM-CSF to IL-1 + TNFα stimulated cultures had no effect on the expansion of HPP-CFC but did result in larger increases in LPP-CFC. TNFα had no effect on the expansion of progenitor [190,191,[193][194][195][196]266] . Figures 13 and 14). ...
The regulation of murine hematopoiesis by the cytokines granulocyte (G)-colony stimulating factor (CSF), macrophage (M)-CSF, granulocyte-macrophage-CSF, kit-ligand (KL), interleukin (IL)-1β, IL-3, IL-6, IL-11, human interleukin for the DA cell line (HILDA), tumor necrosis factor (TNF)α, interferon (IFN)γ, and transforming growth factor-β was studied. Using in vitro clonogenic (CFU-C) and suspension culture (∆-culture) assays it was demonstrated that the proliferation of primitive progenitors with a high proliferative capacity (HPP-CFC) was synergistically stimulated by combinations of growth factors. Among the 68 cytokine combinations tested in the CFU-C and/or the ∆-culture assays the combination of IL-1β + IL-6 + KL was notable in its synergistic stimulation of the growth of HPP-CFC and the expansion of progenitors in ∆-cultures. The transplantation of bone marrow (BM) expanded in ∆-cultures by IL-1β + IL-6 + KL demonstrated that the ex vivo expansion of BM resulted in an accelerated reconstitution of peripheral blood cells in lethally irradiated mice relative to mice transplanted with fresh BM. Furthermore, no impairment of stem cell function was observed as a result of the short-term growth of BM in vitro. These results suggest a clinical use for BM expansion in BM transplantation protocols and in the generation of hematopoietic progenitors for the treatment of iatrogenic cytopenias. The potential use of ∆-cultures in ex vivo BM purging protocols, which attempt to rid benign hematopoietic tissue of malignant cells, was demonstrated using a murine model system. The addition of the cytokines G-CSF and IL-6 as well as all-trans retinoic acid, which were shown to induce the terminal differentiation of the myelomonocytic leukemic cell line WEHI 3B D+ clone 2.8, to IL-1β + IL-6 + KL stimulated ∆-cultures containing BM and WEHI 3B D+ clone 2.8 cells demonstrated that differentiation inducing agents can reduce the number of leukemic cells without the loss of normal hematopoietic progenitors. Lastly, the ability of TNFα, M-CSF, IL-1β and IFNγ to stimulate the recovery or protect murine hematopoietic tissues when given prior to irradiation or 5-fluorouracil treatment was demonstrated.
Vita. Thesis (Ph. D.)--Cornell University, May, 1993. Includes bibliographical references (leaves 226-248).
... A significant role in developing and maintaining a persistent inflammatory response and in the process of joint destruction in JIA is attributed to cytokines [1]. A key cytokine involved in the pathogenesis of JIA is tumour necrosis factor-alpha (TNF-α), which can stimulate the expression of other proinflammatory cytokines, including interleukins IL-1β, IL-6, and IL-8, leading to a protracted inflammatory response [2,3]. In the normal physiological state, proinflammatory cytokines, including TNF-α, are sustained in a state of balance with anti-inflammatory cytokines, such as IL-10. ...
Objective
To determine the dynamics of serum levels of TNF-α in patients with juvenile idiopathic arthritis (JIA) treated with anti-TNF-α biological drugs and investigate their association with the disease activity.
Methods
We conducted a single-centre, observational cohort study in 98 patients with JIA (30 boys, 68 girls, mean age 11.3 years) treated with anti-TNF-α biological drugs. Clinical examinations and laboratory assessments of serum levels of TNF-α were performed before starting therapy with biological drug and at 6-month intervals afterwards up to 2.5 years.
Results
The analysis of serum levels of TNF-α in relation to the disease activity states showed the highest mean serum levels of TNF-α in patients on etanercept who had low disease activity states and in patients on adalimumab who had inactive disease. The correlation analysis in patients with JIA treated with etanercept or adalimumab showed a weak negative correlation between the serum levels of TNF-α and JADAS10 scores ( p = 0.007), ( r = − 0.177).
Conclusion
The assessment of serum levels of TNF-α in children with JIA during treatment with etanercept or adalimumab is not a reliable biomarker of disease activity or immunological remission. Longitudinal measurement of TNF-α has no added clinical value in patients with JIA treated with anti-TNF-α biological drugs. Key Points • There is limited evidence regarding the effect of anti-TNF therapy on serum concentrations of TNF-α in patients with juvenile idiopathic arthritis • Our study showed an increase in the serum level of TNF-α after the initiation of therapy with either etanercept or adalimumab, which was more significant in patients with inactive or low disease activity • Serum TNF-α is most likely not biologically active during therapy with TNF-α inhibitors and therefore not a reliable biomarker of disease activity or immunological remission in patients with juvenile idiopathic arthritis
... The concentration of IL-10 required for 50% suppression averaged 0.35 +: 0.12 unit/ ml (three experiments) and was therefore approximately 10fold higher than for suppression of TNF release (0.04 unit/ m l k 0.01 unit/ml, four experiments). TNF has been reported to induce IL-1 in murine macrophages (35,36). Therefore, we tested the possibility that the suppression of IL-1 release by IL-10 might be mediated through its suppression of TNF production. ...
Transforming growth factor (TGF)-beta and interleukin (IL)-10 inhibited lipopolysaccharide (LPS)-induced macrophage production of the inflammatory cytokines tumor necrosis factor-alpha (TNF), IL-1 alpha, and IL-1 beta by contrasting post-transcriptional mechanisms. TGF-beta acted slowly and late, as it required 12-16 h to exert a suppressive effect, and inhibited TNF production even when added 6 h after LPS. TGF-beta affected neither the level of TNF mRNA, the release of preformed TNF nor the degradation of TNF. Thus, TGF-beta appeared to inhibit translation of TNF mRNA. IL-10 not only suppressed TNF release to a 25-fold greater extent than TGF-beta, but also inhibited release of IL-1. In contrast to TGF-beta, IL-10 acted on an early step in cytokine production, its effect being maximal 3 h after addition of LPS. Unlike TGF-beta, IL-10 markedly suppressed TNF, IL-1 alpha, and IL-1 beta mRNA levels. However, this was accomplished without suppressing transcription of the corresponding genes. Moreover, cycloheximide antagonized the IL-10-dependent reduction in cytokine mRNA levels. Thus, IL-10 may induce a ribonuclease active on cytokine transcripts or may induce a protein that enhances the susceptibility of TNF, IL-1 alpha, and IL-1 beta mRNAs to ribonucleolytic action. We conclude that IL-10 and TGF-beta induce different phenotypes of macrophage deactivation, and deactivate macrophages by different mechanisms: IL-10 promotes degradation of cytokine mRNA, while TGF-beta primarily suppresses translation.
... A s murine homologs of these proteins become available, or if it is determined that the human proteins can act on murine cells, we will evaluate this possibility. Finally it should be noted that, in contrast with other reports of IL-1 induction by IL-1 itself (37,38) a [ 16,[39][40][41][42] in various cell types, we were unable to observe IL-1 bioactivity induction in PEC by either of these cytokines. ...
We have previously reported that IL-3, a cytokine produced by both Th1 and Th2 type CD4+ T cells, displays macrophage-activating potential. IL-3, like IFN-gamma, readily induced functions related to Ag presentation (e.g., Ia and lymphocyte function-associated Ag-1 expression). However, in contrast to the response elicited by IFN-gamma, tumor cytotoxicity was not induced by IL-3. In this paper we have evaluated the capacity of IL-3 to regulate IL-1 expression. Our data demonstrate that although IL-3 alone was unable to induce the production of substantial IL-1 bioactivity in peritoneal exudate cells, it contributed synergistically to the induction of IL-1 bioactivity in the presence of suboptimal doses of LPS. It was of interest that IFN-gamma, which can also interact synergistically with LPS, was unable to complement the partial signals provided by IL-3 for the expression of IL-1 bioactivity, suggesting that IL-3 and IFN-gamma may be providing similar stimulatory signals in this respect. Our studies on the mechanism of synergy between IL-3 and LPS indicated that the effect of LPS did not appear to be mediated by the well-characterized LPS-inducible cytokines of macrophage origin (i.e., IL-1, alpha and beta, TNF-alpha, and IL-6). The best characterized function of IL-3 is its multicolony-stimulating activity as a CSF; in this context we also studied granulocyte-macrophage CSF and noted that it behaves similarly to IL-3 in that it can synergistically contribute to IL-1 induction. A similar, but more dramatic induction of IL-1 synthesis in response to IL-3 was demonstrated by the P388.D1 murine macrophage cell line. The kinetics and the molecular mechanism of the response of P388.D1 to IL-3 indicate several unique features of IL-3-induced IL-1 expression: 1) IL-3 itself induced IL-1 mRNA expression, which was unaccompanied by substantial production of bioactivity, either cell-associated or secreted into the culture supernatant; 2) IL-3 synergized with suboptimal doses of LPS to induce not only heightened IL-1 mRNA levels but bioactivity as well; and 3) IL-3, when combined with LPS, altered the kinetics of IL-1 message and bioactive protein production in response to LPS: IL-3 and LPS induced an early release (3 to 7 h poststimulation) of the IL-1 protein as well as a second peak of mRNA and bioactivity (at 12 to 36 h), which was not observed in response to either IL-3 or LPS alone.(ABSTRACT TRUNCATED AT 400 WORDS)
... First, while either adhesion or culture with LPS are excellent inducers for IL-1 expression by macrophages, these T cell-independent signals have no effect on B cells (12.32). Second, although both macrophages and B cells are stimulated by T cell-dependent mechanisms to express IL-1 (9, 32). the T cell product inducing this effect in either case is different: TNF for macrophages, and other cells (33)(34)(35)(36)(37)4 and, as shown here, IL-2 for B cells. Third, kinetics of induction in vitro indicate that macrophages exhibit maximal mIL-1 within 2 to 6 h (12), whereas for B cells this takes tion of macrophage IL-1 during antigen presentation. ...
Murine splenic B cells did not constitutively express IL-1 activity. After culture with anti-Ig and T cell-conditioned media and then fixation, B cells expressed membrane IL-1 and were able to stimulate growth of the IL-1-dependent T cell clone D10. Expression of membrane IL-1 required stimulation of B cells for 2 days before fixation. Significant IL-1 activity was detectable in freeze-thaw lysates of identical B cell preparations by 12 h. B cells also released IL-1 into the culture media. In situ hybridization studies by using probes to murine IL-1 alpha and IL-1 beta genes supported these observations. Thus, messenger RNA for IL-1 alpha and IL-1 beta rose in parallel, were detected between 6 and 24 h of culture, and declined to low levels by 30 h. Despite the presence of mRNA for IL-1 alpha and IL-1 beta, only IL-1 alpha had functional activity as determined by the use of a mAb to IL-1 alpha. IL-2 was found to be an essential component of the T cell-derived supernatant. Although IL-4 or TNF did not induce significant B cell IL-1 expression, they both caused a modest, but reproducible enhancement when added in combination with IL-2. IFN-gamma, by contrast, partially inhibited IL-1 induction.
The ability of malignant tumors to disseminate to organs distant from the site of the primary lesions is the principal reason for failure in cancer therapy.(1) There are several reasons for this high failure rate. First, at the time of initial diagnosis, metastatic lesions may be too small to detect using currently available diagnostic methodologies; second, the anatomic location of the metastatic lesion may limit the dose of antineoplastic drug that can reach the site without excessive toxicity; and third, the heterogeniety of tumor cell phenotypes within a single lesion is sufficiently diverse, that the responsiveness of cells from one lesion to an antineoplastic modality can differ from both the primary lesion and other metastases.(2–4) This latter issue suggests that the development of an effective therapy for metastatic disease approaches that will circumvent the problems of cellular heterogenicity.
In gram negative bacterial infection, endotoxin is thought to play a principal role in severe pathogenic changes such as hypotension, shock, disseminated intravascular coagulation and multiple organ failure. In the field of quality control of medicine, endotoxin is known as "pyrogen" and it is an important issue to prevent the contamination especially for the injection. Since endotoxin is derived from widely existing bacteria in the environment, contamination occurs easily. In addition, the elimination or inactivation of the toxin is difficult because the toxin survives as a quite stable substance even if the bacteria are sterilized. This review outlines the properties of endotoxin both chemically and biologically, and the quality control of medicine, detection method and measures against the contamination of endotoxin are discussed on the basis of accumulated scientific knowledge of endotoxin.
The aim of this study was to investigate the augmentative effect of a streptoccal preparation, OK432, on the immunological competence of hepatic macrophages. We found that OK432 was distributed predominantly to hepatic macrophages after intravenous injection, and Northern blot analysis revealed that OK432 induced the gene expression of IL-1α, β, and TNFα in the liver. The induction of mRNAs was evident 1 h after the intravenous injection of OK432 and their accumulation reached a maximal level at 3 h. TNF production of hepatic macrophages was also increased by the intravenous injection of OK432. Furthermore, OK432 significantly increased the proportion of IL-2 receptor-positive hepatic macrophages. As for antitumor activity in the liver being augmented by OK432, the cytotoxic and cytostatic activity of hepatic macrophages from OK432-treated rats against tumor cells was significantly increased and OK432 markedly reduced the number of tumor nodules in the liver after the inoculation of tumor cells via the portal vein. These findings, which indicated that OK432 has various immuno-stimulating actions on hepatic macrophages, leading to the augmentation of antitumor activity in the liver, suggest that OK432 may be of some benefit in helping to prevent hepatic metastasis, at least in part, via its activation of hepatic macrophages.
The growth of T lymphocyte colonies in agar is dependent on the cooperation of a number of different cell types and their products. Among these interacting cells are monocytes and/or macrophages. Monocytes are capable of producing both interleukin 1 (IL-1) and tumor necrosis factor (TNF). These two factors display a positive influence on T cell colony formation. Recombinant IL-1 and recombinant TNF were both shown to stimulate T cell colony growth in a dose-dependent manner, and this stimulation could be blocked by prior incubation with anti-IL-1 or anti-TNF, respectively. In addition, conditioned medium obtained from monocytes cultured in the presence of endotoxin also stimulated T cell colony formation. This stimulation by monocyte-conditioned medium was partially suppressed by incubation with anti-TNF or anti-IL-1, while incubation with both antibodies together displayed greater suppression. In conclusion, monocytes produce at least two factors, IL-1 and TNF, which can stimulate T cell colony formation by peripheral blood lymphocytes.
TNF inhibitors have revolutionized the treatment of psoriasis vulgaris as well as psoriatic and rheumatoid arthritis and Crohn disease. Despite our understanding that these agents block TNF, their complex mechanism of action in disease resolution is still unclear.
To analyze globally the genomic effects of TNF inhibition in patients with psoriasis, and to compare genomic profiles of patients who responded or did not respond to treatment.
In a clinical trial using etanercept TNF inhibitor to treat psoriasis vulgaris (n = 15), Affymetrix gene arrays were used to analyze gene profiles in lesional skin at multiple time points during drug treatment (baseline and weeks 1, 2, 4, and 12) compared with nonlesional skin. Patients were stratified as responders (n = 11) or nonresponders (n = 4) on the basis of histologic disease resolution. Cluster analysis was used to define gene sets that were modulated with similar magnitude and velocity over time.
In responders, 4 clusters of downregulated genes and 3 clusters of upregulated genes were identified. Genes downmodulated most rapidly reflected direct inhibition of myeloid lineage immune genes. Upregulated genes included the stable dendritic cell population genes CD1c and CD207 (langerin). Comparison of responders and nonresponders revealed rapid downmodulation of innate IL-1beta and IL-8 sepsis cascade cytokines in both groups, but only responders downregulated IL-17 pathway genes to baseline levels.
Although both responders and nonresponders to etanercept inactivated sepsis cascade cytokines, response to etanercept is dependent on inactivation of myeloid dendritic cell genes and inactivation of the T(H)17 immune response.
Mannoprotein components from Candida albicans were investigated for their ability to induce production of tumor necrosis factor (TNF) by cultured splenocytes from naive or Candida-infected mice. Two chromatographically separated mannoproteins preparations, designated F1 and F2, were as able as the heat-inactivated Candida cells to induce the production of TNF from splenocytes of naive animals. In addition, they caused a significant augmentation of basic TNF secretion by splenocytes of Candida-infected animals. Experiments using plastic and/or nylon wool adherence, as well as treatments with antibodies depleting T or NK cells, consistently indicated that most if not all TNF was produced by splenic macrophages. In cultures of splenocytes from Candida-infected mice, mannoprotein addition also stimulated interferon-gamma (IFN-gamma) production by Thy 1.2 positive cells. Depletion of these cells or addition of anti-IFN-gamma antibodies abolished IFN production and reduced TNF secretion by adherent cells to the levels found in the cultures of mannoprotein-stimulated spleen cells from naive mice. These data add further evidence to the immunomodulatory properties possessed by some cell wall constituents of the human commensal microorganism C. albicans and suggest that IFN-gamma is endowed with a regulatory role in TNF production by mouse macrophages in vitro.
We described in a previous study two pathways by which Th cells induced macrophage membrane IL-1(mIL-1) during Ag presentation. One pathway was lymphokine-independent and mediated by cell-cell contact. The second was lymphokine-dependent. We have now characterized this lymphokine and show that it belongs to the TNF family of proteins. All TH1 and most TH2 clones produced the lymphokine, although TH1 levels were markedly greater. Both types of clones also induced macrophage mIL-1 by cell-cell contact (i.e., in the absence of lymphokine release). Examination of macrophages by in situ hybridization showed that both IL-1 alpha and IL-1 beta mRNA were coordinately induced during Ag presentation to either TH1 or TH2 clones.
We have investigated the release of tumor necrosis factor-alpha (TNF-alpha) by human mononuclear cells (MNC) and isolated human monocytes/macrophages stimulated with S- and R-form lipopolysaccharide (LPS), natural lipid A, and natural and synthetic partial structures thereof. We found that LPS of Salmonella minnesota (S. min.) Rb2, which represents a partial structure of wildtype LPS of Salmonella abortus equi (S.a.e.) lacking the O-chain and parts of the outer core region, was the most active inducer of all substances tested, even more active than the wildtype LPS. Lipid A also induced the production of TNF-alpha by monocytes/macrophages but was less active than wildtype LPS. The natural Escherichia coli (E. coli) type hexaacyl lipid A (compound 506) was more active than the natural S. min. type heptaacyl lipid A (compound 516). The 1- and 4'-monodephospho partial structures (compounds 505 and 504) of E. coli lipid A were less active and represented the smallest structures tested that were able to induce TNF-alpha release by monocytes/macrophages. Synthetic tetraacyl lipid A precursor Ia of E. coli lipid A, lacking non-hydroxylated fatty acids (compound 406), and the monosaccharide precursor lipid X did not induce the release of TNF-alpha in MNC or isolated monocytes/macrophages. This might indicate that the ability of a lipid A structure to induce the release of TNF-alpha is closely connected with the conditions to be at least hexaacylated and/or to contain hydroxylated fatty acids. These results demonstrate a structure-dependent hierarchy of LPS and natural or synthetic partial structures in their capacity of inducing TNF-alpha release by monocytes/macrophages.
The BJC is owned by Cancer Research UK, a charity dedicated to understanding the causes, prevention and treatment of cancer and to making sure that the best new treatments reach patients in the clinic as quickly as possible. The journal reflects these aims. It was founded more than fifty years ago and, from the start, its far-sighted mission was to encourage communication of the very best cancer research from laboratories and clinics in all countries. The breadth of its coverage, its editorial independence and it consistent high standards, have made BJC one of the world's premier general cancer journals. Its increasing popularity is reflected by a steadily rising impact factor.
The antitumor activity of combination therapy with recombinant tumor necrosis-alpha (rhTNF-alpha) and recombinant interleukin-2 (rhIL-2) was assessed against established immunogenic (MCA-106) and nonimmunogenic (MCA-102) sarcomas at both s.c. and visceral (hepatic) sites. C57BL/6 (B6) mice were treated with a single i.v. dose of rhTNF-alpha (2, 4, 6, or 8 micrograms) followed by rhIL-2 (25,000 U) i.p. thrice daily for 5 consecutive days. Synergistic effects as measured by regression of tumor, prolongation of survival, and improved cure rates were found using the combination of rhTNF-alpha plus rhIL-2 compared to rhTNF-alpha alone or rhIL-2 alone in the treatment of the immunogenic sarcoma MCA-106. No significant antitumor effects were observed against the nonimmunogenic MCA-102 sarcoma. These findings were similar for both s.c. and large single hepatic tumor models. The effect of the timing of rhIL-2 injections in relation to rhTNF-alpha administration (concurrent, 2, 4, or 6 days post single rhTNF-alpha dose) was also evaluated. Substantial tumor regression and increased survival times were seen in mice with s.c. tumors when rhIL-2 therapy was delayed as much as 48 h after rhTNF-alpha administration. No antitumor response was noted with the combination compared to rhTNF-alpha alone when rhIL-2 was delayed for greater than 4 days. No increase in lethal toxicity during treatment course of the combination of rhTNF-alpha and rhIL-2 was noted at any schedule compared to single agent rhTNF-alpha therapy. A possible role of rhTNF-alpha in regulation of IL-2-dependent antitumor activity in vivo is discussed.
The effect of recombinant human interleukin 4 (rhIL-4) on the induction in vitro of human lymphokine activated killer cell (LAK) activity was investigated. Peripheral blood mononuclear cells (PBMC) from normal healthy donors were incubated for 4 days with or without recombinant human interleukin-2 (rhIL-2) in the presence or absence of rhIL-4. LAK activity was measured against the NK-resistant colon adenocarcinoma cell line SW742, and NK mediated cytotoxicity was determined using NK sensitive K562 cells. Unlike previous reports using mouse effector cells, rhIL-4 neither induced LAK activity nor augmented the cytotoxic response induced by rhIL-2. In four out of six experiments there was a significant reduction of rhIL-2 induced LAK in the presence of rhIL-4, accompanied by a reduction of Tac antigen expression by rhIL-2 activated cells. Recombinant hIL-4 failed to influence the effector phase of the activated PBMC against SW742 or K562 targets.
This review addresses the multifunctional effects of interleukin-1 in human physiology and its pathogenetic role in several diseases, including neoplasia.
Feline infectious peritonitis (FIP) infection resulting in clinical signs is invariably fatal despite clinical intervention. As FIP is an immune-mediated disease, treatment is mainly aimed at controlling the immune response triggered by the infection with the feline coronavirus (FCoV). Immune suppressive drugs such as prednisone or cyclophosphamide may slow disease progression but do not produce a cure. In nearly every published case report of attempted therapy for clinical FIP, glucocorticoids have been used; there are, however, no controlled studies that evaluate the effect of glucocorticoids as a therapy for FIP. Some veterinarians prescribe immune modulators to treat cats with FIP with no documented controlled evidence of efficacy. It has been suggested that these agents may benefit infected animals by restoring compromised immune function, thereby allowing the patient to control viral burden and recover from clinical signs. However, a non-specific stimulation of the immune system may be contraindicated as clinical signs develop and progress as a result of an immune-mediated response to the mutated FCoV.
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