Inhibition of LPS and <i>Plasmodium falciparum</i> Induced Cytokine Secretion by Pentoxifylline and Two Analogues

Jakobsen, Palle; Koch, Claus; Bendtzen, Klaus

doi:10.1046/j.1365-3083.1997.d01-425.x

Cited by 5 publications

(5 citation statements)

References 29 publications

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“…In conclusion, our data show that HWA 448 limited muscle wasting by suppressing the activation of Ub-proteasome-dependent proteolysis, which plays a prominent role in the breakdown of muscle proteins, and was much more potent than pentoxifylline. In addition, HWA 448 did not alter peripheral blood mononuclear cell viability, and has a longer serum half-life and presumably lower toxicity than pentoxifylline, which is commonly used in humans [52]. Taken together, the data suggest that the administration of HWA 448 may contribute to the prevention of the muscle wasting seen in cancer and other catabolic states characterized by a hyperproduction of TNF, such as sepsis or trauma.…”

Section: Discussionmentioning

confidence: 84%

Torbafylline (HWA 448) inhibits enhanced skeletal muscle ubiquitin‒proteasome-dependent proteolysis in cancer and septic rats

Combaret¹,

Tilignac²,

Claustre³

et al. 2002

Biochem. J.

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The development of new pharmacological approaches for preventing muscle wasting in cancer is an important goal because cachectic patients display a reduced response to chemotherapy and radiotherapy. Xanthine derivatives such as pentoxifylline inhibit tumour necrosis factor-alpha (TNF) production, which has been implicated in the signalling of muscle wasting. However, the effect of pentoxifylline has been inconclusive in clinical trials. We report here the first direct evidence that daily injections of torbafylline (also known as HWA 448), another xanthine derivative, had no effect by itself on muscle proteolysis in control healthy rats. In cancer rats, the drug blocked the lipopolysaccharide-induced hyperproduction of TNF and prevented muscle wasting. In these animals HWA 448 suppressed the enhanced proteasome-dependent proteolysis, which is sensitive to the proteasome inhibitor MG132, and the accumulation of high-molecular-mass ubiquitin (Ub) conjugates in the myofibrillar fraction. The drug also normalized the enhanced muscle expression of Ub, which prevails in the atrophying muscles from cancer rats. In contrast, HWA 448 did not reduce the increased expression of either the 14 kDa Ub conjugating enzyme E2 or the ATPase and non-ATPase subunits of the 19 S regulatory complex of the 26 S proteasome, including the non-ATPase subunit S5a, which recognizes polyUb degradation signals. Finally, the drug also prevented muscle wasting in septic rats (which exhibit increased TNF production), and was much more potent than pentoxifylline or other xanthine derivatives. Taken together, the data indicate that HWA 448 is a powerful inhibitor of muscle wasting that blocks enhanced Ub-proteasome-dependent proteolysis in situations where TNF production rises, including cancer and sepsis.

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Section: Discussionmentioning

confidence: 84%

Torbafylline (HWA 448) inhibits enhanced skeletal muscle ubiquitin‒proteasome-dependent proteolysis in cancer and septic rats

Combaret¹,

Tilignac²,

Claustre³

et al. 2002

Biochem. J.

View full text Add to dashboard Cite

show abstract

“…In addition, HWA 448 did not alter peripheral blood mononuclear cell viability, and has a longer serum half-life and presumably lower toxicity than pentoxifylline, which is commonly used in humans [52]. Taken together, the data suggest that the administration of HWA 448 may contribute to the prevention of the muscle wasting seen in cancer and other catabolic states characterized by a hyperproduction of TNF, such as sepsis or trauma.…”

Section: Discussionmentioning

confidence: 84%

Torbafylline (HWA 448) inhibits enhanced skeletal muscle ubiquitin–proteasome-dependent proteolysis in cancer and septic rats

Combaret

Tilignac

Claustre

et al. 2002

Biochemical Journal

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The development of new pharmacological approaches for preventing muscle wasting in cancer is an important goal because cachectic patients display a reduced response to chemotherapy and radiotherapy. Xanthine derivatives such as pentoxifylline inhibit tumour necrosis factor-α (TNF) production, which has been implicated in the signalling of muscle wasting. However, the effect of pentoxifylline has been inconclusive in clinical trials. We report here the first direct evidence that daily injections of torbafylline (also known as HWA 448), another xanthine derivative, had no effect by itself on muscle proteolysis in control healthy rats. In cancer rats, the drug blocked the lipopolysaccharide-induced hyperproduction of TNF and prevented muscle wasting. In these animals HWA 448 suppressed the enhanced proteasome-dependent proteolysis, which is sensitive to the proteasome inhibitor MG132, and the accumulation of high-molecular-mass ubiquitin (Ub) conjugates in the myofibrillar fraction. The drug also normalized the enhanced muscle expression of Ub, which prevails in the atrophying muscles from cancer rats. In contrast, HWA 448 did not reduce the increased expression of either the 14kDa Ub conjugating enzyme E2 or the ATPase and non-ATPase subunits of the 19S regulatory complex of the 26S proteasome, including the non-ATPase subunit S5a, which recognizes polyUb degradation signals. Finally, the drug also prevented muscle wasting in septic rats (which exhibit increased TNF production), and was much more potent than pentoxifylline or other xanthine derivatives. Taken together, the data indicate that HWA 448 is a powerful inhibitor of muscle wasting that blocks enhanced Ub—proteasome-dependent proteolysis in situations where TNF production rises, including cancer and sepsis.

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“…Other laboratories have shown that the specific activation of macrophages decreases septic sequelae and improves survival in humans and experimental animals (3,7,11). Besides human macrophages, other immune-related cells respond to different molecules increasing resistance to infection (23,24,51). In this setting, for example, the involvement of T cells in the enhanced resistance to Klebsiella pneumoniae septicemia in mice treated with liposome-encapsulated muramyl tripeptide has been demonstrated (19).…”

Section: Discussionmentioning

confidence: 99%

ALimulusAntilipopolysaccharide Factor-Derived Peptide Exhibits a New Immunological Activity with Potential Applicability in Infectious Diseases

Vallespí¹,

Glaria²,

Reyes³

et al. 2000

Clin Diagn Lab Immunol

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Previous studies have shown that cyclic peptides corresponding to residues 35 to 52 of the Limulus antilipopolysaccharide (anti-LPS) factor (LALF) bind and neutralize LPS-mediated in vitro and in vivo activities. Therapeutic approaches based on agents which bind and neutralize LPS activities are particularly attractive because these substances directly block the primary stimulus for the entire proinflammatory cytokine cascade. Here we describe new activities of the LALF 31-52 peptide, other than its LPS binding ability. Surprisingly, supernatants from human mononuclear cells stimulated with the LALF peptide are able to induce in vitro antiviral effects on the Hep-2 cell line mediated by gamma interferon (IFN-␥) and IFN-␣. Analysis of the effect of LALF 31-52 on tumor necrosis factor (TNF) and nitric oxide (NO) production by LPS-stimulated peritoneal macrophages revealed that a pretreatment with the peptide decreased LPS-induced TNF production but did not affect NO generation. This indicates that the LALF peptide modifies the LPS-induced response. In a model in mice with peritoneal fulminating sepsis, LALF 31-52 protected the mice when administered prophylactically, and this effect is related to reduced systemic TNF-␣ levels. This study demonstrates, for the first time, the anti-inflammatory properties of the LALF-derived peptide. These properties widen the spectrum of the therapeutic potential for this LALF-derived peptide and the molecules derived from it. These agents may be useful in the prophylaxis and therapy of viral and bacterial infectious diseases, as well as for septic shock.Lipopolysaccharide (LPS) is believed to be the initiator of the systemic inflammatory cascade that culminates in the organ damage and multiorgan failure found in septic patients (17,47). In recent years, attention has been focused on the release by macrophages of cytokines, particularly interleukin 1␤ (IL-1␤), IL-6, and tumor necrosis factor alpha (TNF-␣), that are important mediators of septic shock pathology (9, 39). Recent data have substantially advanced our knowledge on the complex timing and interactions among events like LPS exposure, cytokine release (32), and the development of septic shock. These data strongly involve LPS and macrophage cytokine release as primary effectors in the etiology of septic shock. They also suggest that LPS blockade, cytokine blockade, or specific cytokine modulation may be of therapeutic benefit in septic patients.Therapeutic approaches based on molecules that bind and neutralize LPS are particularly attractive, because they directly block the primary stimulus for the proinflammatory cytokine cascade. Recent studies have mainly involved rBPI (recombinant bactericidal permeability-increasing protein) (1) and peptides derived from it (13, 36). The Limulus anti-LPS factor (LALF) is a small, basic protein found in hemocytes from both Tachypleus tridentatus and Limulus polyphemus, which inhibits the endotoxin-mediated activation of the coagulation cascade (30), apparently by binding to LPS. This prot...

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Inhibition of LPS and Plasmodium falciparum Induced Cytokine Secretion by Pentoxifylline and Two Analogues

Cited by 5 publications

References 29 publications

Torbafylline (HWA 448) inhibits enhanced skeletal muscle ubiquitin‒proteasome-dependent proteolysis in cancer and septic rats

Torbafylline (HWA 448) inhibits enhanced skeletal muscle ubiquitin‒proteasome-dependent proteolysis in cancer and septic rats

Torbafylline (HWA 448) inhibits enhanced skeletal muscle ubiquitin–proteasome-dependent proteolysis in cancer and septic rats

ALimulusAntilipopolysaccharide Factor-Derived Peptide Exhibits a New Immunological Activity with Potential Applicability in Infectious Diseases

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