I. L. Bonta

Involvement of inflammatory mediators in macrophage antitumor activity.

This review describes the potential role of macrophages in defense against cancer cells and the regulatory involvement of inflammatory mediators in this role. Interactions between macrophage‐derived cytokines (tumor necrosis factor a, interleukin‐1, IL‐6) and their interrelationships with eicosanoids (mainly the cyclooxygenase product prostaglandin E2 and some lipoxygenase metabolites) represent a network that controls the expression of antitumor activity of macrophages either in a cell‐to‐cell contact system between the effector and the target tumor cell or as cell‐free soluble products. Attention is given to the influence of tumor burden on production of cytokines and eicosanoids by macrophages and to the production of these mediators by tumor cells. Emphasis is placed on the roles of TNF‐α and PGE2 in links between inflammatory and antitumor functions of macrophages. Finally, the perspectives and still existing problems in clinical implications of macrophage‐derived cytokines are discussed in terms of a conceivable macrophage‐directed immunotherapy of cancer.

Slow wave sleep and a state resembling absence epilepsy induced in the rat by γ-hydroxybutyrate

Abstract The effect of γ-hydroxybutyrate (GHB) in relatively low doses (12.5–200 mg/kg) on sleep stages, electrocorticogram (ECoG) patterns and behavior was investigated in the rat. 50–100 mg/kg GHB induced slow wave sleep but, in contrast to the cat, not paradoxical sleep. 200 mg/kg induced a hypersynchronous, bilaterally symmetrical ECoG pattern, which was different in amplitude and frequency distribution from normally occuring high amplitude patterns. When the hypersynchrony occured in bursts, the rats displayed a sudden arrest of motor behavior. Convulsions were not induced. The results, together with the finding of others that GHB is a natural constituent of mammalian brain and our previous observation that the GHB-induced hypersynchrony can be antagonized by anti-absence (anti-petit mal) drugs are discussed in view of the possibility that GHB might play a role in the etiology of absence epilepsy in man.

Immunomodulatory-antiinflammatory functions of E-type prostaglandins. Minireview with emphasis on macrophage-mediated effects.

The biological transformation of arachidonic acid (AA) leads to a wide array of physiologically active products which are involved in several aspects of the inflammatory process. Depending upon various factors, including its anatomical location, arachidonic acid undergoes biotransformation by the membrane-bound enzyme cyclo-oxygenase and by cytoplasmic lipoxygenase enzymes. The capacities of the prostaglandins PGE2 and PGD2 and of prosta- cyclin (PGI2)--all derived via the cyclo-oxygenase pathway--to enhance the vascular-exudative com- ponent of inflammation have been most extensively studied. Furthermore, substances such as the hydroxy acid 12-HETE and particularly the recently discovered leukotrienes--all generated via the lipoxygenase pathways--are markedly chemotactic and contribute to cellular infiltration during inflam- mation. Thus, the majority of established concepts of inflammation emphasize these and other metabolites of AA as proinflammatory substances. The fact that inhibitors of cyclo-oxygenase are powerful anti- inflammatory agents is also telling evidence in favour of the above view, which has gained additional momentum from more recent observations, suggest- ing that similar anti-inflammatory drugs may also counteract the formation of at least some lipoxy- genase products (Atkinson & Collier, 1980). Never- theless, the view that the inflammatory process is exclusively promoted by metabolites of AA is over- simplified. Evidence is accumulating that, depending on the experimental situation that is studied, PGE2 displays either pro- or anti-inflammatory effects (Morley, 1979; Bonta & Parnham, 1978, 1980). While such a dual function has not been convincingly shown for other products of AA-bioconversion, the bis-homo-gamma-linoleic acid derived PGEI does share this property with PGE2 (Kunkel, Thrall, Kunkel, McCormick, Ward & Zurier, 1979; Bonta & Parnham, 1978, 1980). AA and bis-homo-gamma- linoleic acid are essential fatty acids (EFA) and EFAs

Antagonism of gamma-hydroxybutyrate-induced hypersynchronization in the ECoG of the rat by anti-petit mal drugs

Administration of gamma-hydroxybutyrate (GHB) (200 mg/kg i.p.) in rats evoked a hypersynchronous electrocorticogram pattern which was antagonized by specific anti-petit mal agents, while other antiepileptic drugs exerted no influence, or even potentiated the effect of GHB. The specific sensitivity of the GHB-induced hypersynchrony to anti-petit mal agents suggests a possible use of this effect as a model for testing potential anti-petit mal agents.

Reduced exudation and increased tissue proliferation during chronic inflammation in rats deprived of endogenous prostaglandin precursors

Two models of chronic inflammation were studied in rats deprived of endogenous precursors of prostaglandins by feeding the animals on essential fatty acid deficient (EFAD) food. During kaolin-induced pouch-granuloma, exudate production was markedly reduced in EFAD rats, when compared with normal animals. The exudates from normal rats contained large amounts of PGE, but in the exudates from EFAD rats the amount of PGE was very markedly reduced. Similarly, with carrageenan-impregnated polyether sponges, the exudative component of inflammation was reduced in EFAD rats. However, the proliferative component was significantly increased, particularly in relation to the stunted growth of EFAD rats. Sponge exudates from EFAD rats contained fewer leucocytes than those from normal animals but the fall in leucocyte count was much smaller than the very marked reduction in PGE activity. EFAD rats also exhibited a significant increase in adrenal weights. The results are discussed in the light of the ambivalent (pro- or anti-inflammatory) role of endogenous PGS. It appears that, in the proliferative phase of inflammation, the anti-inflammatory role of PGs is more dominant.

Acute anti-inflammatory effects of aspirin and dexamethasone in rats deprived of endogenous prostaglandin precursors

Paw oedema, induced by carrageenan, was potentiated in normal rats by arachidonic acid and bishomo‐γ‐linoleic acid, but not by 5,8,11‐eicosatrienoic acid. The latter is not an endogenous prostaglandin precursor, but replaces the other two in essential fatty acid deficient (EFAD) rats. Carrageenan oedema was partially suppressed in these EFAD rats. Aspirin exhibited equal suppression of carrageenan oedema in both normal and EFAD rats, despite the fact that, in the latter, prostaglandins are of negligible importance. The anti‐inflammatory effect of dexamethasone was also identical in both normal and EFAD rats. The view that interference with the prostaglandin‐system explains the acute anti‐inflammatory effects of the two drugs, is discussed, in relation to the present results.

Receptors involved n the action of 5-HT and tryptamine on the isolated rat stomach fundus preparation

Abstract Participation of α-adreniceptors in the effects of 5-HT and tryptamine on the isolated rat stomach fundus preparation was investigated. The effects of recognized anti-5-HT agents were also investigated to determine whether or not the same type of receptors was involved in the response of the rat fundus to 5-HT and tryptamine. Methylsergide was shown to be a very active, slowly reversible inhibitor of the 5-HT-induced contrations. The degree of inhibition was dependent on the time of pre-incubation and reached its maximum after approximately 2 hr. The α-adrenolytic agent piperoxan appeared to be a competitive antagonist of 5-HT. Piperoxan was able to prevent or reduce the anti-5-HT activity of mianserin, cyproheptadine and methysergide, indicating a common site of all action. All antagonists affected the 5-HT contractions more than those induced by tryptamine. It is concluded, that the effect of 5-HT on the isolated rat stomach fundus is the result of an interaction of 5-HT with one type of receptor. This receptor probably is the classical D-tryptamine receptor. The response to tryptamine is the result of an interaction by tryptamine with two different types of receptors. One type of receptors is identical to the receptor mediating the response to 5-HT, whilst the other type of receptor is more resistant to inhibition by emthylsergide, piperoxan, cyproheptadine or mianserin, and might be identical with the PRT-receptor, described earlier as being resistant to inhibition by phenoxybenzamine.

Essential fatty acid deficiency: A condition to discriminate prostaglandin and non-prostaglandin mediated components of inflammation

The carrageenin induced hind paw inflammation is partially suppressed in essential fatty acid deficient (EFAD) rats, but prostaglandin E1 produces larger paw oedema in EFAD rats than in normal ones. Arachidonic acid restores in EFAD rats the suppressed carrageenin inflammation. Shortage of prostaglandin-precursor is the underlying mechanism of reduced carrageenin inflammation in EFAD rats, while the prostaglandin-synthesizing capacity remains unimpaired. BPP9a, a bradykinin potentiating peptide, enhances the carrageenin inflammation in EFAD and control rats equally. The kinin-mediated component of tissue injury is unaltered in EFAD animals, in which the prostaglandin-phase of inflammation is selectively suppressed. Indomethacin does not further reduce in EFAD rats that particular phase of inflammation where prostaglandins are abolished due to precursor shortage. In the preceding period indomethacin exerts partial suppression of inflammation even in EFAD rats. The latter finding supports the view that inhibition of prostaglandin-biosynthesis does not fully explain the antiinflammatory effect of indomethacin.

Endotoxin‐stimulated peritoneal macrophages obtained from continuous ambulatory peritoneal dialysis patients show an increased capacity to release interleukin‐1βin vitro during infectious peritonitis

Abstract. Interleukin‐1 (IL‐1) release by peritoneal macrophages obtained from patients on continuous ambulatory peritoneal dialysis (CAPD) was studied in nine patients during an infection‐free period and eight patients during an infectious peritonitis, using an ELISA for IL‐ 1β. Without exogenous stimulation with LPS, peritoneal macrophages from infected and unin‐fected patients released the same amounts of IL‐lβ, 183pM40 pg ml‐1 24 h‐1) per 106 cells (means + SEM) and 251 pM 6 pg ml‐1, respectively. However, in response to a dose of 5 μg ml‐1 of LPS, peritoneal macrophages released significantly more (P < 0.005) IL‐1β during peritonitis (6579 β 2793 pg ml‐1 24 h‐1 per 106 cells) compared with the infection‐free period (1040 pM 182 pg ml‐1). These findings show that after microbial invasion of the peritoneal cavity, peritoneal macrophages are primed in vivo to release an increased amount of IL‐lβin vitro after subsequent exogenous stimulation with LPS, indicating that peritoneal mac‐rophage activation for IL‐1β secretion occurs in steps.,

Prostaglandin E2 inhibits the release of tumor necrosis factor-α, rather than interleukin 1β, from human macrophages

Abstract We have reported previously that macrophages obtained from renal patients on continuous ambulatory peritoneal dialysis (CAPD) during an episode of infectious peritonitis display a decrease in intracellular cAMP levels and in spontaneous in vitro release of PGE 2 and PGI 2 . Such macrophages also release large quantities of IL-1β and TNFα when stimulated in vitro by LPS. In view of the interregulatory effects between PGE 2 and macrophage cytokines (IL-1β and TNFα) in their production, we examined in the present work to what extent the LPS-induced release of either IL-1β or TNFα in vitro from CAPD-originated peritoneal macrophages is affected by graded doses of exogenous PGE 2 (range 0 – 1000 ng/ml) and by the cyclooxygenase inhibitor indomethacin (INDO) (10 −6 M). IL-1β and TNFα were determined using an enzyme-linked immunoabsorbent assay and an immunoradiometric assay, respectively. We found that PGE 2 invariably induced a dose-dependent decrease in TNFα release. In peritoneal macrophages collected during an infection-free period, TNFα release decreased from 3225 pg/ml (controls) to 353 pg/ml at 1000 ng/ml of PGE 2 , and in peritoneal macrophages collected during an episode of infectious peritonitis, it decreased from 4100 pg/ml (controls) to 545 pg/ml at 100 ng/ml of PGE 2 . However, PGE 2 failed to influence the secretion of IL-1β. INDO induced an approx, two-fold increase in TNFα release, but had no effect on IL-1β release. These findings indicate that exogenous and endogenous PGE 2 controls the release of TNFα rather than IL-1β from LPS-stimulated peritoneal macrophages.