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Neuropeptide-leukocyte interactions: Examples of pharmacological modulation
Pharmacological Research, Vol . 26, Supplement 2,1992
42
NELRUPFPTTIDE-LEUKOCYTE IN1ERACTICNS : FCAMPIES OF PMMOOLJGICAL M3D)LATICN *Sandra Brunelleschi, *Elisabetta Ceni & Roberto Fantozzi Dept . Pharmacology, Univ . Florence, V .le G .B . hbrgagni, 65 - 50136 F RFNZE ; Inst . Pharmacology and Pharmacognosy, Univ . Turin, Corso Raffaello, 31- 10125 TORM Keywords : substance P
neurokinin A
Neurogenic inflammation, tachykinins substance P, neurons,
ijwu oregulaticn
which involves the release of neuropeptides
(including the
SP, and neurokinin A, NKA) from capsaicin-sensitive primary sensory
is thought to contribute to several inflammatory diseases in the airways,
skin,
joints, gut, etc . [1] . At least three different tachykinin receptor types, namely NK-1, NK-2 and NK-3,
have been recognized due to their ability to be activated by natural agonists SP,
NKA and neurokinin B (NKB),
respectively :
the development of specific agonists and
antagonists to these receptors has further supported this classification neuropeptides
[2] .
SP and other
have been shown to interact with inflammatory and immune cells
[2] ; we
previously reported [3] that mammalian tachykinins activate guinea-pig alveolar macrophages (AMs) in vitro, a NK-2 receptor being involved, and that SP and NKA dose-dependently enhanced Platelet Activating Factor (PAF)-evoked superoxide anion neutrophils (Pmts), NU
(0') 2
production from
human
being ineffective [4] .
To further investigate the immmEregulatory role of tachykinins, we compared the effects of sensory neuropeptides in AMs obtained from control or ovalbumin-sensitised guinea-pigs . By testing 0' production and thranboxane B (TXB ) release from AMs, the cncentratiarresponse 2 2 2 curves for NKA and SP were shifted to the left, three orders and one order of magnitude, respectively,
in cells obtained from sensitised animals, with no variation on maximal
effects . ED
values for NKA- evoked TXB release were 0 .4 nM in control AMs and 0 .2 pM in 50 2 sensitised cells ; similar results were obtained by evaluating 0' production . The involvement 2 of a NK-2 receptor was confirmed by the observation that the dose-response curve for the NK-2 8 selective receptor agonist, [R-Ala ]--NM(4-10) was moved leftwards, maximal effects being significantly enhanced in AMs obtained from sensitised guinea-pigs .
Moreover,
the
cyclopeptide L659,877, a selective NK receptor antagonist, significantly reduced NKA-evoked 2
1043-6618/92/26110042-02/$03 .00/0
© 1992 The Italian Pharmacological Society
Pharmacological Research, Vol . 26, Supplement 2, 1992 0 - production in both control and sensitised AMs . On the contrary, AM activation evoked by 2 9 [Sar ]-SP sulfone, a NK-1 receptor agonist, was small and did not differ significantly in both groups . The bacterial peptide N-formylmethionyl-leucyl-phenylalanine (FMLP) dosedependently evoked 0- production in AMs : neither maximal effects nor ED s ( 10 .9 nM in 2 50 control and 11 .6 nM in sensitised cells) were significantly different . Therefore, AMs from sensitised guinea-pigs show enhanced responsiv en'c s to tachykinins, but not to another peptidergic stimulus, such as FMLP . We previously reported [4] that mammalian tachykinins dose-dependently enhanced PAF-evoked 0 2 production in human Ms, with an order of potency (SP > NKA > NKB =inactive) , which might suggest NK-1 receptor activation . However, these priming effects were recorded at concentrations higher than those at which tachykinins activate their receptors in other system
[2,
4] .
To solve this problem, we evaluated the ability of tachykinin selective 9 8 agonists to exert priming effects . Neither [Sar ]-SP sulfone nor [a-Ala ]-NKA(4-10) were able to trigger an enhanced respiratory burst in PMNs challenged with PAF or EMU, thus suggesting that SP-evoked effects an human M s are not receptor-mediated . As a consequence, the cyclopeptide L668,169, which is referred to as a potent NK-1 antagonist [2], only minimally reduced SP-evoked priming effects in human PMNs- Therefore, mechanism(s) other than receptorlinked activation are presumed for tachykinin-PMN interaction . Such an interaction could probably be ascribable to direct activation of G--proteins by basic amino acid residues, as previously demonstrated for mast cells [2] .
According to results obtained in leukocytes, a
role for tachykinins as modulators of inflammatory cells can be established, further confirming the close interrelationship between inflammation and neural control .
REFEREN [1] Barnes PJ, Belvisi MG, Rogers DF . Modulation of neurogenic inflammation : novel approaches to inflammatory diseases . Trends Pharmacol Sci 1990, 11 : 185-9 . [2] Frossard N, Advenier C . Tachykinin receptors and the airways . Life Sci 1991, 49 : 1941- 53 . [3] Brunelleschi 3, Vanni L, Ledda F, Giotti A, Maggi CA, Fantozzi R . Tachykinins activate guinea-pig alveolar macrophages : involvement of NK2 and NK1 receptors . Br J Pharmacol 1990, 100 : 417-20 . [4] Brunelleschi S, Tarli S, Giotti A, Fantozzi R . Priming effects of mammalian tachykinins on human neutrophils . Life Sci 1991, 48 : PL1 - PL5 .
43
42
NELRUPFPTTIDE-LEUKOCYTE IN1ERACTICNS : FCAMPIES OF PMMOOLJGICAL M3D)LATICN *Sandra Brunelleschi, *Elisabetta Ceni & Roberto Fantozzi Dept . Pharmacology, Univ . Florence, V .le G .B . hbrgagni, 65 - 50136 F RFNZE ; Inst . Pharmacology and Pharmacognosy, Univ . Turin, Corso Raffaello, 31- 10125 TORM Keywords : substance P
neurokinin A
Neurogenic inflammation, tachykinins substance P, neurons,
ijwu oregulaticn
which involves the release of neuropeptides
(including the
SP, and neurokinin A, NKA) from capsaicin-sensitive primary sensory
is thought to contribute to several inflammatory diseases in the airways,
skin,
joints, gut, etc . [1] . At least three different tachykinin receptor types, namely NK-1, NK-2 and NK-3,
have been recognized due to their ability to be activated by natural agonists SP,
NKA and neurokinin B (NKB),
respectively :
the development of specific agonists and
antagonists to these receptors has further supported this classification neuropeptides
[2] .
SP and other
have been shown to interact with inflammatory and immune cells
[2] ; we
previously reported [3] that mammalian tachykinins activate guinea-pig alveolar macrophages (AMs) in vitro, a NK-2 receptor being involved, and that SP and NKA dose-dependently enhanced Platelet Activating Factor (PAF)-evoked superoxide anion neutrophils (Pmts), NU
(0') 2
production from
human
being ineffective [4] .
To further investigate the immmEregulatory role of tachykinins, we compared the effects of sensory neuropeptides in AMs obtained from control or ovalbumin-sensitised guinea-pigs . By testing 0' production and thranboxane B (TXB ) release from AMs, the cncentratiarresponse 2 2 2 curves for NKA and SP were shifted to the left, three orders and one order of magnitude, respectively,
in cells obtained from sensitised animals, with no variation on maximal
effects . ED
values for NKA- evoked TXB release were 0 .4 nM in control AMs and 0 .2 pM in 50 2 sensitised cells ; similar results were obtained by evaluating 0' production . The involvement 2 of a NK-2 receptor was confirmed by the observation that the dose-response curve for the NK-2 8 selective receptor agonist, [R-Ala ]--NM(4-10) was moved leftwards, maximal effects being significantly enhanced in AMs obtained from sensitised guinea-pigs .
Moreover,
the
cyclopeptide L659,877, a selective NK receptor antagonist, significantly reduced NKA-evoked 2
1043-6618/92/26110042-02/$03 .00/0
© 1992 The Italian Pharmacological Society
Pharmacological Research, Vol . 26, Supplement 2, 1992 0 - production in both control and sensitised AMs . On the contrary, AM activation evoked by 2 9 [Sar ]-SP sulfone, a NK-1 receptor agonist, was small and did not differ significantly in both groups . The bacterial peptide N-formylmethionyl-leucyl-phenylalanine (FMLP) dosedependently evoked 0- production in AMs : neither maximal effects nor ED s ( 10 .9 nM in 2 50 control and 11 .6 nM in sensitised cells) were significantly different . Therefore, AMs from sensitised guinea-pigs show enhanced responsiv en'c s to tachykinins, but not to another peptidergic stimulus, such as FMLP . We previously reported [4] that mammalian tachykinins dose-dependently enhanced PAF-evoked 0 2 production in human Ms, with an order of potency (SP > NKA > NKB =inactive) , which might suggest NK-1 receptor activation . However, these priming effects were recorded at concentrations higher than those at which tachykinins activate their receptors in other system
[2,
4] .
To solve this problem, we evaluated the ability of tachykinin selective 9 8 agonists to exert priming effects . Neither [Sar ]-SP sulfone nor [a-Ala ]-NKA(4-10) were able to trigger an enhanced respiratory burst in PMNs challenged with PAF or EMU, thus suggesting that SP-evoked effects an human M s are not receptor-mediated . As a consequence, the cyclopeptide L668,169, which is referred to as a potent NK-1 antagonist [2], only minimally reduced SP-evoked priming effects in human PMNs- Therefore, mechanism(s) other than receptorlinked activation are presumed for tachykinin-PMN interaction . Such an interaction could probably be ascribable to direct activation of G--proteins by basic amino acid residues, as previously demonstrated for mast cells [2] .
According to results obtained in leukocytes, a
role for tachykinins as modulators of inflammatory cells can be established, further confirming the close interrelationship between inflammation and neural control .
REFEREN [1] Barnes PJ, Belvisi MG, Rogers DF . Modulation of neurogenic inflammation : novel approaches to inflammatory diseases . Trends Pharmacol Sci 1990, 11 : 185-9 . [2] Frossard N, Advenier C . Tachykinin receptors and the airways . Life Sci 1991, 49 : 1941- 53 . [3] Brunelleschi 3, Vanni L, Ledda F, Giotti A, Maggi CA, Fantozzi R . Tachykinins activate guinea-pig alveolar macrophages : involvement of NK2 and NK1 receptors . Br J Pharmacol 1990, 100 : 417-20 . [4] Brunelleschi S, Tarli S, Giotti A, Fantozzi R . Priming effects of mammalian tachykinins on human neutrophils . Life Sci 1991, 48 : PL1 - PL5 .
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