Spermine inhibition of monocyte activation and inflammation
M Zhang1, L V Borovikova, H Wang
1The Picower Institute for Medical Research, Manhasset, New York 11030, USA. mzhang@picower.edu
Abstract:
The innate immune system functions as a defensive front line against pathogenic invasion, but the proinflammatory products of activated monocytes and macrophages (e.g., TNF and NO) can also injure normal cells. Anti-inflammatory mediators restrain the innate immune response and prevent excessive collateral tissue damage. Spermine, a ubiquitous biogenic polyamine, specifically and reversibly suppresses the synthesis of monocyte proinflammatory cytokines. This may provide a counterregulatory mechanism to restrain monocyte activation in injured or infected tissues and in tumors where spermine levels are significantly increased. Here we show that monocyte spermine uptake was significantly increased following lipopolysaccharide stimulation. The polyamine analogue 1, 4-bis(3-aminopropyl)-piperazine (BAP) inhibited LPS-stimulated monocyte spermine uptake via the "nonselective" polyamine transporter. BAP fully restored macrophage TNF synthesis despite the presence of spermine, indicating that the mechanism of monocyte deactivation by spermine is dependent on spermine uptake. Administration of BAP in vivo significantly augmented the development of carrageenan-induced paw edema and nitric oxide release. Thus, endogenous spermine normally inhibits the innate inflammatory response by restraining macrophages.
Insights
Spermine, a natural compound, limits the innate immune response by reducing inflammatory cytokine production in monocytes. This mechanism is crucial for preventing excessive tissue damage during inflammation and in tumors.
Area of Science:
- Immunology
- Molecular Biology
- Biochemistry
Background:
- The innate immune system, including monocytes and macrophages, protects against pathogens but can cause collateral tissue damage through proinflammatory mediators like TNF and NO.
- Anti-inflammatory mediators are essential for controlling innate immune responses and preventing excessive tissue injury.
- Spermine, a biogenic polyamine, is known to suppress monocyte proinflammatory cytokine synthesis, potentially acting as a counterregulatory mechanism in conditions like infection, injury, and tumors.
Purpose of the Study:
- To investigate the role of spermine uptake in monocyte deactivation.
- To elucidate the mechanism by which spermine inhibits monocyte proinflammatory cytokine synthesis.
- To determine the in vivo relevance of spermine-mediated inhibition of innate immune responses.
Main Methods:
- Monocyte spermine uptake was measured following lipopolysaccharide (LPS) stimulation.
- The polyamine analogue 1,4-bis(3-aminopropyl)-piperazine (BAP) was used to inhibit spermine uptake.
- Macrophage TNF synthesis was assessed in the presence of spermine and BAP.
- Carrageenan-induced paw edema and nitric oxide release were measured in vivo following BAP administration.
Main Results:
- Monocyte spermine uptake significantly increased after LPS stimulation.
- BAP inhibited LPS-stimulated monocyte spermine uptake, indicating the involvement of a nonselective polyamine transporter.
- BAP treatment restored macrophage TNF synthesis despite the presence of spermine, confirming that spermine's deactivating effect depends on its uptake.
- In vivo administration of BAP enhanced carrageenan-induced paw edema and nitric oxide release.
Conclusions:
- Endogenous spermine normally inhibits the innate inflammatory response by suppressing macrophage activation.
- Spermine's inhibitory effect on monocytes is dependent on its cellular uptake via a nonselective polyamine transporter.
- Targeting spermine uptake represents a potential strategy for modulating inflammatory responses.
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