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. 2010 May;51(5):1075-84.
doi: 10.1194/jlr.M003236. Epub 2009 Nov 15.

A role for inflammatory mediators in heterologous desensitization of CysLT1 receptor in human monocytes

Valérie Capra  1 , Maria Rosa Accomazzo, Fabrizio Gardoni, Silvia Barbieri, G Enrico Rovati
Affiliations

A role for inflammatory mediators in heterologous desensitization of CysLT1 receptor in human monocytes

Valérie Capra et al. J Lipid Res. 2010 May.

Abstract

Cysteinyl-leukotrienes (cysteinyl-LT) are rapidly generated at sites of inflammation and, in addition to their role in asthma, rhinitis, and other immune disorders, are increasingly regarded as significant inflammatory factors in cancer, gastrointestinal, cardiovascular diseases. We recently demonstrated that in monocyte/macrophage-like U937 cells, extracellular nucleotides heterologously desensitize CysLT(1) receptor (CysLT(1)R)-induced Ca(2+) transients. Given that monocytes express a number of other inflammatory and chemoattractant receptors, this study was aimed at characterizing transregulation between these different stimuli. We demonstrate that in U937 cells and in primary human monocytes, a series of inflammatory mediators activating G(i)-coupled receptor (FPR1, BLT(1)) desensitize CysLT(1)R-induced Ca(2+) response unidirectionally through activation of PKC. Conversely, PAF-R, exclusively coupled to G(q), cross-desensitizes CysLT(1)R without the apparent involvement of any kinase. Interestingly, G(s)-coupled receptors (beta(2)AR, H(1/2)R, EP(2/4)R) are also able to desensitize CysLT(1)R response through activation of PKA. Heterologous desensitization seems to affect mostly the G(i)-mediated signaling of the CysLT(1)R. The hierarchy of desensitization among agonists may be important for leukocyte signal processing at the site of inflammation. Considering that monocytes/macrophages are likely to be the major source of cysteinyl-LT in many immunological and inflammatory processes, shedding light on how their receptors are regulated will certainly help to better understand the role of these cells in orchestrating this complex network of integrated signals.

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Figures

Fig. 1.
Fig. 1.
Desensitization of CysLT1R by fMLF- and LTB4-activated Gi-coupled receptors. (A) Effect of increasing concentration of fMLF (1st challenge) on 10 nM LTD4-induced [Ca2+]i transient. (B) Reversal of fMLF-induced heterologous CysLT1R desensitization by pretreatment with GFX (5 min) and complete prevention PTX (300 ng/ml, overnight).( C) Effect of pretreatment with GFX (5 min) and PTX (300 ng/ml, overnight) on the LTB4-induced densensitization of the [Ca2+]i transient evoked by 10 nM LTD4 (2nd challenge). Values shown represent means of [Ca2+]i stimulation over basal (s/b) ± SEM of at least three independent experiments. Statistical comparison of multiple groups was performed using one-way ANOVA followed by Bonferroni's multiple comparison test (**P < 0.01, versus control, unless otherwise indicated). GFX, GF109203X.
Fig. 2.
Fig. 2.
Desensitization of CysLT1R by PAF-activated Gq-coupled receptor. (A) Desensitization of the LTD4-induced [Ca2+]i response (2nd challenge) by 36 nM PAF and lack of effect of pretreatment with increasing concentrations of GFX (5 min). (B) Effect of pretreatment with 10 μM WEB 2086 (WEB, 5 min) on the PAF-induced desensitization of the [Ca2+]i transient evoked by 10 nM LTD4 (2nd challenge). Values shown represent means of [Ca2+]i stimulation over basal (s/b) ± SEM of at least three independent experiments. Statistical comparison of multiple groups was performed using one-way ANOVA followed by Bonferroni's multiple comparison test (*P < 0.05; **P < 0.01, versus control, unless otherwise indicated). (C) Effect of increasing concentrations of YM-254890 on PAF-induced CysLT1R heterologous desensitization. Values shown represent means ± SEM of three independent experiments. GFX, GF109203X.
Fig. 3.
Fig. 3.
Impact of CysLT1R activation on fMLF-, LTB4- and PAF-induced [Ca2+]i transient. Representative traces of the [Ca2+]i transient induced by 1 μM fMLF (A), 1 μM LTB4 (B) and 36 nM PAF (C) (2nd challenge) before or after an initial challenge with 10 nM LTD4.
Fig. 4.
Fig. 4.
Desensitization of CysLT1R by isoproterenol-activated Gs-coupled receptors. (A) Effect of increasing concentration of isoproterenol (iso) (1st challenge) on 10 nM LTD4-induced [Ca2+]i transient. (B) Reversal of 1 μM iso-induced heterologous CysLT1R desensitization by pretreatment with GFX or H89 (5 min). C) Effect of pretreatment with 10 μM propanolol (prop) 5 min on 1 μM iso-induced desensitization of the [Ca2+]i transient evoked by 10 nM LTD4 (2nd challenge). Values shown represent means of [Ca2+]i stimulation over basal (s/b) ± SEM of at least three independent experiments. Statistical comparison of multiple groups was performed using one-way ANOVA followed by Bonferroni's multiple comparison test (**P < 0.01, vs. control, unless otherwise indicated). GFX, GF109203X.
Fig. 5.
Fig. 5.
Desensitization of CysLT1R by PGE2- and histamine- activated Gs-coupled receptors. Effect of pretreatment with GFX and H89 (5 min) on 1 μM PGE2 (A) or histamine (hist) (B) induced desensitization of the [Ca2+]i transient evoked by 10 nM LTD4 (2nd challenge). Values shown represent means of [Ca2+]i stimulation over basal (s/b) ± SEM of at least three independent experiments. Statistical comparison of multiple groups was performed using one-way ANOVA followed by Bonferroni's multiple comparison test (**P < 0.01, vs. control, unless otherwise indicated). GFX, GF109203X.
Fig. 6.
Fig. 6.
Effect of forskolin (fsk) pretreatment on LTD4-induced [Ca2+]i transient. Representative traces of the effect of a prior challenge with vehicle (A), 1 μM (B), 10 μM (C) and 100 μM (D) forskolin on [Ca2+]i transient induced by 10 nM LTD4.
Fig. 7.
Fig. 7.
Impact of CysLT1R activation on fMLF-, PAF- and isoproterenol-induced [Ca2+]i transient in human primary monocytes. (A) Effect of 1 μM fMLF (1st challenge) on 100 nM LTD4-induced [Ca2+]i transient and effect of pretreatment with PTX (300 ng/ml, overnight). (B) Effect of 36 nM PAF (1st challenge) on 100 nM LTD4-induced [Ca2+]i transient and effect of pretreatment with 100 μM WEB 2086 (WEB, 5 min). (C) Effect of 10 μM isoproterenol (iso) (1st challenge) on 100 nM LTD4-induced [Ca2+]i transient and effect of pretreatment with 10 μM propanolol (prop) 5 min. Values shown represent means of [Ca2+]i stimulation over basal (s/b) ± SEM of at least three independent experiments. Statistical comparison of multiple groups was performed using one-way ANOVA followed by Bonferroni's multiple comparison test (**P < 0.01, vs. control).
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