THE acyl carrier coenzyme A (CoA) is involved in fatty acid metabolism. The carnitine/CoA ratio is of particular importance in regulating the transport of long-chain fatty acids into mitochondria for oxidation. Also CoA has a role in the formation and breakdown of products from both the cyclooxygenase and lipoxygenase pathways of the precursor arachidonic acid. In the present study the effect of 4 days feeding of 300 mg/kg/day of L-carnitine, acetyl Lcarnitine and propionyl L-carnitine on the basal and calcium ionophore (A23187) stimulated release of arachidonic acid metabolites from rat carrageenin elicited peritoneal cells was investigated. There were two series of experiments carried out. In the first, the harvested peritoneal cell population consisted of less than 90% macrophages and additional polymorphonuclear (PMN) leucocytes. The basal release of prostaglandin E2 (PGE2), 6-ketoprostaglandin F1&#945; (6-keto-PGF1&#945;) and leukotriene B4 (LTB4) was stimulated by all treatments. The A23187 stimulated release of 6-keto-PGF1&#945; and LTB4 was increased by all three compounds. The 6-keto-PGF1&#945;:TxB2 and 6-keto-PGF1&#945;:LTB4 ratios were increased by carnitine treatment. These results suggested that carnitine could modify the macrophage component of an inflammatory site in vivo. In the second series of experiments the harvested cell population was highly purified (&#62;95% macrophages) and none of the compounds fed to the rats caused a change of either eicosanoid or TNF&#945; formation. Moreover the 6-keto-PGF1&#945;:TxB2 and 6-keto-PGF1&#945;:LTB4 ratios were not enhanced by any of the compounds tested. It is conceivable that in the first series the increased ratios 6-keto-PGF1&#945;:TxB2 and 6-keto-PGF1&#945;:LTB4 reflected the effect of carnitine or its congeners on PMN leucocytes rather than on macrophages.

Ingrid M. Garrelds

Graham R. Elliott

Wanda M. Pruimboom

Freek J. Zijlstra

Iv&#225;n L. Bonta

Effects of carnitine and its congeners on eicosanoid discharge from rat cells: implications for release of TNF&#945;

The ability of carnitine congeners to modulate cytokine production by human peripheral blood mononuclear cells (PBMC) was investigated. Modulation of cytokine production by PBMC of young (30 years of age or younger) and old (70 years of age or older) normal donors was first compared. The PBMC were collected over Ficoll&#8211;Hypaque and incubated in the presence of various concentrations of acetyl L-carnitine for 24 h. Subsequently the supernatants were collected and examined for cytokine production. The presence of cytokines in tissue culture supernatants was examined by ELISA. The cytokines measured included IL-1&#945;, IL-1&#946;, IL-2, IL-4, IL-6, TNF&#945;, GM&#8211;CSF, and IFN&#947;. The results showed that at 50 &#956;g/ml of acetyl L-carnitine the most significant response was obtained for TNF&#945;. In this regard four of five young donors responded, but only one of five old donors responded. More recently these studies were expanded to examine the ability of L-carnitine to modulate cytokine production at higher doses, 200 and 400 &#956;g/ml, in young donors. The results of these studies showed that in addition to TNF&#945;, significant production of IL-1&#946; and IL-6 was observed. These preliminary studies provide evidence that carnitine may modulate immune functions through the production of selected cytokines.

Nicola M. Kouttab

Claudio  De Simone

Modulation of cytokine production by carnitine

The purpose of this study was to determine if free or esterified carnitine could alter fatty acid metabolism and ameliorate sepsis in lipopolysaccharide (LPS)-treated rats. Throughout a 96 h observation post-LPS, i.p. administration of both markedly reduced illness and accelerated recovery. Carnitine prevented the acute LPS-induced rise in serum triglycerides (45 &#177; 6, 59 &#177; 5 vs. 83 &#177; 8 mg/ml, p &#60; 0.001), respectively. This difference was accompanied by a significant increase in liver lipogenesis in LPS controls compared to both carnitines and normal rats (6.1 &#177; 0.3 vs. 3.9 &#177; 0.5, 4.3 &#177; 0.5, and 1.8 &#177; 0.4 &#956;mol/h, respectively, p &#60; 0.04). Compared to normal rats, total liver carnitine was significantly elevated in LPS controls and even higher in the carnitine groups (357 &#177; 40 vs. 736 &#177; 38, 796 &#177; 79, and 1081 &#177; 21 nmol/g). The data suggest that carnitines may be of therapeutic value in sepsis treatment and one action may be to partition fatty acids from esterification to oxidation.

Linda L. Gallo

Yan  Tian

Zaven  Orfalian

Gary  Fiskum

Amelioration of popolysaccharide-induced sepsis in rats by free and esterified carnitine

The authors demonstrated that in vivo administered L-carnitine strongly ameliorated the immune response in both healthy individuals receiving Intralipid and ageing subjects with cardiovascular diseases, as shown by the enhancement of mixed lymphocyte reaction. Notably, in the latter group L-carnitine treatment also resulted in a significant reduction of serum levels of both cholesterol and triglycerides. Therefore, the hypothesis is that L-carnitine supplementation could ameliorate both the dysregulated immune response and the abnormal lipid metabolism in several conditions.

Giuseppe  Famularo

Sonia  Tzantzoglou

Gino  Santini

Vito  Trinchieri

Sonia  Moretti

Aleardo  Koverech

L-carnitine: a partner between immune response and lipid metabolism &#63;

The literature presented illustrates that lipopolysaccharide (LPS), from bacterial cell walls, induces tumour necrosis factor (TNF) synthesis in macrophages. TNF affects a number of cell types, amongst which are endothelial cells, within a few hours. Its injection has been shown to produce all symptoms of the toxic syndrome. In the present communication the vulnerability of endothelial cells will be stressed. These cells require carnitine not only for fatty acid oxidation but also for membrane protection and repair. As endothelial cells lose carnitine during hypoperfusion, it is speculated that the supply of carnitine during the early phase of LPS toxicity in rats might delay or avoid loss of endothelial functions. Earlier it was observed that hearts from rats, injected 3 h previously with LPS, showed strongly increased interstitial fluid production compared to hearts from control rats, even when TNF was present during a 3 h in vitro perfusion. It showed that LPS in vivo generates factors other than TNF, such as platelet activating factor (PAF), that are responsible for the increased capillary permeability.

W. C. H&#252;lsmann

Vulnerability of vascular endothelium in lipopolysaccharide toxicity: effect of (acyl) carnitine on endothelial stability

The effect of L-carnitine and some of its acyl derivatives on serum TNF production and lethality in a murine experimental endotoxin shock model was investigated. In some instances, serum IL-6 production was also evaluated. In this experimental model, C57BL/6 mice received 30 mg/kg LPS (E. cell 055:B5) injected intraperitoneally, while L-carnitine and its derivatives were administered according to different schedules. Serum levels of TNF and IL-6 were evaluated 1 h following LPS injection. The treated animals were also monitored daily for differences in body temperature, feeding, and survival for 10 days after LPS injection. Although some derivatives were able to significantly affect TNF production, the marked decrease in serum TNF levels of LPS-treated mice was not paralleled by a substantial increase in survival.

Vito  Ruggiero

Claudio M. D&#39;Urso

Claudio  Albertoni

Silvia  Campo

Piero  Foresta

Edoardo Arrigoni Martelli

LPS-induced serum TNF production and lethality in mice: effect of L-carnitine and some acyl-derivatives

Whole bacteria or bacterial components or their extracts were employed to restore or augment the immune system. Beneficial effects were attained with these agents in treating various diseases. These agents were named biological response modifiers (BRMs) because they regulated certain cellular components of the immune system. The cellular regulation induced by these BRMs was found to be due to cytokines. The cytokines were shown to act directly on the various cellular components and to provide therapeutic benefit in various autoimmune and immune deficiency diseases. Overproduction of specific cytokines however leads to a deleterious effect on the host. Overproduction of tumour necrosis factor (endotoxin, lipopolysaccharide) leads to septic shock. Bacteraemia is the leading cause of overproduction of tumour necrosis factor (TNF). Septic shock in many cases leads to death. Several monoclonal antibodies to lipopolysaccharide (LPS) and anticytokines have demonstrated protection against septic shock.

Michael A. Chirigos

Immunoregulatory biological response modifiers: effect of cytokines on septic shock

Endotoxins (lipopolysaccharides, LPS) are agents of pathogenicity of Gram-negative bacteria, implicated in the development of Gram-negative shock. Endotoxin reacts with lipopolysaccharide-sensitive cells producing endogenous mediators such as tumour necrosis factor alpha (TNF&#945;). Macrophages are cells mediating the toxic activities of LPS and TNF&#945; is the primary mediator of the lethal action of endotoxin. This review article discusses the various mechanisms by which endotoxin hypersensitivity in bacteria-sensitized animals develops. The paper concludes with a discussion on the possible protective effect of carnitine congeners against the lethal action of LPS.

C.  Galanos

M. A. Freudenberg

Bacterial endotoxins: biological properties and mechanisms of action

Tuberculosis (TBC) is characterized by a complex immune response which parallels the clinical course of the disease. In this respect, acquired resistance, delayed hypersensitivity reaction and anergy are the main types of immune reactivity to mycobacterial antigens. In view of the presence of nonspecific and specific immune deficits in TBC patients, a clinical trial was carried out in a group of 20 individuals with active pulmonary TBC by oral administration of acetyl-L-carnitine (ALC). This drug, which has been shown to possess immunomodulating activities, was able to upregulate the T-dependent antibacterial activity in TBC patients after 30 days&#39; treatment, while the same activity decreased in patients receiving placebo only. On the other hand, ALC did not modify serum levels of tumour necrosis factor-&#945;, in the same individuals. This cytokine plays a detrimental rather than beneficial role in TBC pathogenesis. In the light of these data, ALC seems to be a powerful immunomodulator in the course of Mycobacterium tuberculosis infection and other mycobacteriosis.

Emilio  Jirillo

Maria  Altamura

Carlo  Marcuccio

Cosimo  Tortorella

Salvatore  Antonaci

Immunological responses in patients with tuberculosis and in vivo effects of acetyl-L-carnitine oral administration

The effect of carnitine, a drug that plays an essential role in mitochondria metabolism, on some of the most important human polymorphonuclear leucocytes (PMN) activation steps including modulation of adhesion molecule density, reactive oxygen species production, and tumour necrosis factor-&#945; (TNF&#945;) production was investigated. The capability of carnitine in protecting PMN from deter ioration on storage was also studied. Data shows that carnitine exerts considerable effects on all PMN functions investigated. Although the ultimate effect was often donor dependent, TNF&#945; production was exceptional in that carnitine was able to consistently reduce TNF&#945; production in Staphylococcus aureus stimulated PMN in a clear dose-dependent fashion. It is concluded that carnitine may represent a useful active agent in situations characterized by PMN mobilization/activation.

Andrea  Fattorossi

Roberto  Biselli

Anna  Casciaro

Claudio  de Simone

Regulation of normal human polyrnorphonuclear leucocytes by carnitine

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Mediators of Inflammation publishes papers on all types of inflammatory mediators, including cytokines, histamine, bradykinin, prostaglandins, leukotrienes, PAF, biological response modifiers and the family of cell adhesion-promoting molecules

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