Neuropeptide substance P upregulates chemokine and chemokine receptor expression in primary mouse neutrophils.
Neuropeptides play an important role in the active communication between the nervous and immune systems. Substance P (SP) is a prominent neuropeptide involved in neurogenic inflammation and has been reported to exert various proinflammatory actions on inflammatory leukocytes including neutrophils. The present study further investigated the modulatory effect of SP (1 muM) on chemokine production and chemokine receptor expression in primary mouse neutrophils. Our results showed that SP primed neutrophils for chemotactic responses not only to the CXC chemokine macrophage inflammatory protein (MIP)-2/CXCL2 but also to the CC chemokine MIP-1alpha/CCL3. The activating effect of SP on neutrophils was further evidenced by upregulation of the CD11b integrin, the activation marker of neutrophils. SP induced both the mRNA and protein expression of the chemokines MIP-1alpha/CCL3 and MIP-2/CXCL2 in neutrophils and upregulated the chemokine receptors CC chemokine receptor (CCR)-1 and CXC chemokine receptor (CXCR)-2. This stimulatory effect on chemokine and chemokine receptor expression in neutrophils was further found to be neurokinin-1 receptor (NK-1R) specific. Pretreatment with selective NK-1R antagonists inhibited SP-triggered activation of neutrophils and chemokine and chemokine receptor upregulation. Moreover, SP-induced chemokine upregulation was NF-kappaB dependent. SP time dependently induced NF-kappaB p65 binding activity, IkappaBalpha degradation, and NF-kappaB p65 nuclear translocation in neutrophils. Inhibition of NF-kappaB activation with its inhibitor Bay11-7082 (10 muM) abolished SP-induced NF-kappaB binding activity and upregulation of MIP-1alpha/CCL3 and MIP-2/CXCL2 in neutrophils. Together, these results suggest that SP exerts a direct stimulatory effect on the expression of chemokines and chemokine receptors in mouse neutrophils. The effect is NK-1R mediated, involving NF-kappaB activation.
Sun
Jia
J
Dept of Pharmacology, National University of Singapore, Yong Loo Lin School of Medicine, Centre for Life Sciences, Singapore,
Ramnath
Raina Devi
RD
Bhatia
Madhav
M
D021581:Active Transport, Cell Nucleus; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D039481:CD11b Antigen / Q000096:biosynthesis; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D019742:Chemokines, CC / Q000096:biosynthesis; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis; D008297:Male; D051379:Mice; D015213:Neuroimmunomodulation; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D054389:Receptors, CCR1; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000235:genetics; D023063:Receptors, Interleukin-8B / Q000096:biosynthesis; D018040:Receptors, Neurokinin-1 / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013373:Substance P / Q000378:metabolism* / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D001713:Biphenyl Compounds; D039481:CD11b Antigen; C496534:Ccl3 protein, mouse; C515301:Ccr1 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D018925:Chemokines; D019742:Chemokines, CC; C404915:Cxcl2 protein, mouse; D020672:I-kappa B Proteins; D019402:Macrophage Inflammatory Proteins; D009570:Nitriles; D012333:RNA, Messenger; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D023063:Receptors, Interleukin-8B; D018040:Receptors, Neurokinin-1; D011994:Recombinant Proteins; D013450:Sulfones; D051996:Transcription Factor RelA; D013373:Substance P; C066892:CP 96345