Inhibitory effects of low molecular weight heparin on mediator release by mast cells: preferential inhibition of cytokine production and mast cell-dependent cutaneous inflammation.
There has been substantial evidence that suggests that heparin may modulate various aspects of immune function and inflammation in addition to its well known anticoagulant activity. In this regard heparin was found to suppress cell-mediated immune responses or asthmatic reactions to allergen challenge. In the present study we analyse the effects of low molecular weight heparin (LMWH) on mast cell degranulation and cytokine production in vitro and on the elicitation of IgE-mediated mast cell-dependent late cutaneous allergic inflammation in vivo. We have established that LMWH preferentially inhibited tumour necrosis factor-alpha (TNF-alpha) and IL-4 production without having any significant effect on mast cell degranulation. These effects have been observed in mast cells derived from three different origins that were activated by either immunological or non-immunological stimuli. We have shown that there is inhibition of TNF-alpha production (and not neutralization of activity), as elimination of the drug after a short preincubation and addition of LMWH to rTNF-alpha had no effect on TNF-alpha-mediated cytotoxic activity. These results were also confirmed by ELISA. In vivo, s.c. injection of the LMWH inhibited the leucocyte infiltration associated with the late cutaneous response which followed passive cutaneous anaphylaxis (PCA) reaction, without affecting mast cell numbers or degranulation. These data suggest that LMWH may have an inhibitory role in mast cell-mediated allergic inflammation, and thus might be considered as a possible therapeutic modality.
Baram
D
D
Department of Medicine, Meir General Hospital, Kfar-Saba, Israel.
Rashkovsky
M
M
Hershkoviz
R
R
Drucker
I
I
Reshef
T
T
Ben-Shitrit
S
S
Mekori
Y A
YA
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D015550:Cell Degranulation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis*; D003872:Dermatitis / Q000517:prevention & control*; D005260:Female; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology*; D008407:Mast Cells / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000925:Anticoagulants; D016207:Cytokines; D006495:Heparin, Low-Molecular-Weight; D014409:Tumor Necrosis Factor-alpha