Relationship: 1777



Increased pro-inflammatory mediators leads to Leukocyte recruitment/activation

Upstream event


Increased pro-inflammatory mediators

Downstream event


Leukocyte recruitment/activation

Key Event Relationship Overview


AOPs Referencing Relationship


AOP Name Adjacency Weight of Evidence Quantitative Understanding
Endocytic lysosomal uptake leading to liver fibrosis adjacent High
Increased DNA damage leading to increased risk of breast cancer adjacent Moderate Not Specified
Increased reactive oxygen and nitrogen species (RONS) leading to increased risk of breast cancer adjacent Moderate Not Specified

Taxonomic Applicability


Term Scientific Term Evidence Link
human Homo sapiens NCBI
mouse Mus musculus NCBI

Sex Applicability


Sex Evidence

Life Stage Applicability


Term Evidence
All life stages

Key Event Relationship Description


Circulating blood leukocytes are required to migrate to sites of injury and infection with the aim to eliminate the primary inflammatory trigger and contribute to tissue repair. In this process are involved selectins (expressed both on leukocytes and endothelium) and integrins (expressed on leukocytes) (von Andrian et al., 1991), with the essential role of the vascular endothelium.

Fast activation of the endothelium with inflammatory stimuli such as histamine and PAF (type I) or slow activation with tumor necrosis factor (TNF) or cytokine interleukin-1 β (IL-1β) (type II), makes the surface of endothelium adhesive (Bevilacqua and Gimbrone, 1987; Pober and Sessa, 2007). This transformation is mediated by a transcriptionally regulated program involving the nuclear factor NF-kB dependent pathway triggered by pro-inflammatory cytokines or bacterial endotoxins (reviewed by Collins et al., 1995).

Integrins mediate attachment between cells or to basement membrane. The β2 integrin family is exclusively expressed on leukocytes and is essential for leukocyte arrest on the endothelium and for migration across the endothelium (Ley et al., 2007). In unstimulated leukocytes integrins are usually in a conformation with low binding affinity, until they receive signals from other receptors, such as chemokine receptors (G-protein-coupled receptors), when they change their conformation and display high affinity for ligands (Luo et al., 2007). Chemokines activate β1 or β2 integrins on monocytes, neutrophils, and lymphocytes and as such serve as chemoattractant for these cells during inflammation (Huber et al., 1991; Tanaka et al., 1993; Gunn et al., 1998).

The chemokines are a family of structurally related cytokines that can act as pro-inflammatory agents (Baggiolini et al., 1994; Vaddi et al., 1997). They have the ability to attract leukocyte subsets to specific sites. They recruit neutrophils, monocytes, natural killer cells (NK) and natural killer T (NKT) cells, all of which express inflammatory chemokine receptors and immature dendritic cells (DCs) that provide the link between innate and adaptive immunity (Oo et al., 2010). After antigen-specific activation of lymphocytes by activated DCs, inflammatory chemokines then attract antigen-specific effector T cells to the inflammatory site (Heydtmann and Adams, 2002).

During diapedesis, leukocytes migrate across the endothelium and basement membrane to enter tissue (Ley et al., 2007; Yadav et al., 2003). Once in tissue, the leukocyte follows chemokine gradients to sites of inflammation, using chemokine-mediated changes in the actin cytoskeleton to propel migration. For example, it was demonstrated that chemokines CXCL9, CXCL10 and CXCL11 are important not only in adhesion, but also in transmigration of effectors T lymphocytes through hepatic endothelium (Curbishley et al., 2005; Eksteen et al., 2004). Intracellular actin reorganization is a prerequisite for cell movement, and it has been shown that chemokines such as SDF-1 induce and increase intracellular filamentous actin in lymphocytes (Bleul et al., 1996).

There is essential role of interleukins, but also other factors such as tumor necrosis factor (TNF), interferon (IFN) in leukocyte recruitment and production of chemokines.

Normally, IL-1β binds to IL-1R1 receptor on the surface of target cells. Following ligand binding the adaptor molecule, myeloid differentiation factor-88 (MyD88), interacts with IL-1R1 via its toll interleukin receptor (TIR) domain (O'Neill, 2008). Signal transduction leads to activation of both mitogen-activated protein kinases (MAPKs) and the transcription factor NF-kB, and resulting in pro-inflammatory cytokine expression. For example, chemokine RANTES production requires the transcription factor NF-kB and the activation of mitogen-activated protein kinases (MAPKs) (Genin et al., 2000; Miyamoto et al., 2000; Kujime et al., 2000, Maruoka et al., 2000; Yang et al., 2000).

TNF-α cleavage produces an intracellular domain that translocates to the nucleus and induces pro-inflammatory cytokine signalling, particularly the expression of IL-12 (Friedman et al., 2006). IL-18 induces natural killer and natural killer T cells to produce IFN-γ (Okamura et al., 1998), but it requires IL-12 to induce IFN-γ production by Th1 cells (Nakanishi et al., 2001). There is an essential role of IFN-I in promoting the chronic recruitment of Ly6Chi monocytes. IFN-I production is elicited via a toll like receptor-7 (TLR-7) and MyD88-dependent pathway (Lee et al., 2008).

While CXC-chemokines, e.g. IL-8, act mostly on neutrophils (Springer, 1995), members of the CC-chemokines, e.g. RANTES and macrophage inflammatory protein have been shown to exert function on monocytes, eosinophils and lymphocytes (Baggiolini et al., 1994; Carr et al., 1994). This depends on the receptors that are expressed on leukocytes. Th1 express preferentially CCR5 and CXCR3, while Th2 cells have CCR3, CCR4 and CCR8 on their surface (Syrbe et al., 1999). Monocytes and macrophages express CCR5 and other receptors for RANTES (Weber et al., 2000).

RANTES chemokine is produced by many cells in the extravascular compartment, including fibroblasts, epithelial cells, and tissue-infiltrating lymphocytes and monocytes (MacEwan, 2002; Hehlgans and Männel, 2002; Black et al., 1997). It acts as a potent chemoattractant for monocytes, memory T cells, eosinophils, and basophils (Schall et al., 1988, 1990; Baggiolini and Dahinden, 1994). Elevated levels of RANTES transcripts are detected within hours of exposure to pro-inflammatory stimuli, including IL-1β, TNF-α, IFN-γ, viruses and LPS (Barnes et al., 1996).

Evidence Supporting this KER


Biological Plausibility


There is much evidence that application of chemokines attract leukocytes to specific site in different species (Beck et al., 1997; Lee et al., 2000; Fahy et al., 2001; Nikiforou et al., 2016).

Empirical Evidence


It was shown that a number of chemokines destabilize the rolling of lymphocytes on L-selectin ligands, suggesting that chemokines are capable of regulating the rolling process (Grabovsky et al., 2002).

Jorgensen and colleagues showed that exposure of mice to FliCind strain S. Typhimurium triggered a significant neutrophil influx in the spleen of wild-type mice, but not Il1b/Il18/ mice (Jorgensen et al., 2016).

The expression of chemokines CCL2, CCL7, and CCL12 was reduced dramatically in MyD88-/- mice (Lee et al., 2009).

Miyamoto and colleagues showed that exposure of cells to IL-1β, TNF-α, and IFN-γ resulted in the induction of RANTES mRNA and protein (Ortiz et al., 1996; Miyamoto et al., 2000). The levels of RANTES production by the fibroblasts in the presence of IL-1β or TNF-α were significantly elevated compared with those in the absence of these factors (Yamada et al., 2001).

In the mouse, IFN-γ administration induces high levels of IP-10 expression in liver and kidneys, with lower levels in spleen (Narumi et al., 1992).

CAPE inhibitor of NF-kB blocked partially IL-1β induced expression of chemokines MIP-1a and MIP-1b (Guo et al., 2003).

CCR2 and CCR5 receptors on the CD8 T cells are enriched in the inflamed human liver, and CCR1 is important in the regulation of hepatic inflammation in murine models (Shields et al., 1999; Boisvert et al., 2003).  

Intradermal injection of RANTES induces a potent T-lymphocyte and eosinophils recruitment (Fahy et al., 2001; Beck et al., 1997).  Intradermal administration of MIP-1a resulted in accumulation of monocytes, lymphocytes, eosinophils and recruitment of neutrophils (Lee et al., 2000).

Direct IL-1α exposure to the gut resulted in increased numbers of CD3+ cells in the fetal sheep ileum when compared with control animals on the first day after the exposure. The number of white blood cells, monocytes, and neutrophils was increased in cord blood after 6 days of IL-1α exposure to the lung and chorioamnion/skin. The number of lymphocytes on the day 6 was increased for the lung. Compared with controls, gut mRNA levels of TNF-α and IL-1 was significantly increased at 6 days after IL-1α exposure to the GI tract (Nikiforou et al., 2016).

IL-1 β induced up-regulation of CXCR4 in certain cancer cells, but in order to do so necessary is that these cells have IL-1R1. Presence of IL-1R antagonist significantly inhibited the up-regulation of CXCR4 induced by IL-1β at both mRNA and protein level (Sun et al., 2015).

SDF-1 is an efficacious chemoattractant and showed a similar dose response for murine lymphocytes and human monocytes, but was not active on human or murine neutrophils. SDF-1 is a highly effective transendothelial chemoattractant (Bleul et al., 1996).

Uncertainties and Inconsistencies


Lloyd and colleagues found that several chemokines can stimulate the adherence of peripheral blood lymphocytes to ICAM-1 coated slides (Loyd et al., 1996). However, by using a parallel plate flow chamber, other study failed to observe such an effect (Carr et al., 1996).

Quantitative Understanding of the Linkage


Response-response Relationship




Known modulating factors


Known Feedforward/Feedback loops influencing this KER


Domain of Applicability


Human (Bleul et al., 1996; Miyamoto et al., 2000; Yamada et al., 2001; Sun et al., 2015)

Sheep (Nikiforou et al., 2016)

Mouse (Narumi et al., 1992; Fahy et al., 2001; Lee et al., 2009)



Baggiolini M, Dahinden CA. CC chemokines in allergic inflammation. Immunol. Today (1994) 15:127–133.

Baggiolini M, Dewald B, Moser B. Interleukin-8 and related chemotactic cytokines-CXC and CC chemokines. Adv. Immunol. (1994) 55:97-179.

Barnes DA, Huston M, Holmes R, Benveniste EN, Yong VW, Scholz P, Perez HD. Induction of RANTES expression by astrocytes and astrocytoma cell lines. J. Neuroimmunol. (1996) 71: 207–214.

Beck LA, Dalke S, Leiferman KM, Bickel CA, Hamilton R, Rosen H, Bochner BS, Schleimer RP. Cutaneous injection of RANTES causes eosinophil recruitment: comparison of nonallergic and allergic human subjects. J Immunol. (1997) 159:2962–2972.

Bevilacqua MP, Gimbrone MA Jr. Inducible endothelial functions in inflammation and coagulation. Semin Thromb Hemost. (1987) 13:425–433.

Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF, Castner BJ, Stocking KL, Reddy P, Srinivasan S, Nelson N, Boiani N, Schooley KA, Gerhart M, Davis R, Fitzner, Johnson RS, Paxton RJ, March CJ, Cerretti DP. A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature (1997) 385: 729-733.

Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med. (1996) 184(3): 1101–1109.

Boisvert J, Kunkel EJ, Campbell JJ, Keeffe EB, Butcher EC, Greenberg HB. Liver-infiltrating lymphocytes in end-stage hepatitis C virus: subsets, activation status, and chemokine receptor phenotypes. J Hepatol (2003) 38: 67–75.

Carr MW, Alon R, Springer TA. The C-C chemokine MCP-1 differentially modulates the avidity of beta 1 and beta 2 integrins on T lymphocytes. Immunity (1996) 4: 179–187.

Carr MW, Roth S, Luther E, Rose SS, Springer TA. Monocyte chemoattractant protein-1 is a major T lymphocyte chemoattractant. Pro& Natl. Acad. Sci. USA. (1994) 91:3652-3656.

Collins T, Read MA, Neish AS, Whitley MZ, Thanos D, Maniatis T. Transcriptional regulation of endothelial cell adhesion molecules: NF-kappa B and cytokine-inducible enhancers. FASEB J. (1995) 9:899–909.

Curbishley SM, Eksteen B, Gladue RP, Lalor P, Adams DH. CXCR3 activation promotes lymphocyte transendothelial migration across human hepatic endothelium under fluid flow. Am J Pathol (2005)  167: 887–899.

Eksteen B, Grant AJ, Miles A, Curbishley SM, Lalor PF, Hübscher SG, Briskin M, Salmon M, Adams DH. Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis. J Exp Med (2004) 200: 1511–1517.

Fahy O, Porte H, Sénéchal S, Vorng H, McEuen AR, Buckley MG, Walls AF, Wallaert B, Tonnel AB, Tsicopoulos A. Chemokine-induced cutaneous inflammatory cell infiltration in a model of Hu-PBMC-SCID mice grafted with human skin. Am J Pathol. (2001) 158(3):1053-63.

Friedmann E, Hauben E, Maylandt K, Schleeger S, Vreugde S, Lichtenthaler SF, Kuhn PH, Stauffer D, Rovelli G, Martoglio B. SPPL2a and SPPL2b promote intramembrane proteolysis of TNFα in activated dendritic cells to trigger IL-12 production. Nat. Cell Biol. (2006) 8: 843-848.

Genin P, Algarte M, Roof P, Lin R, Hiscott J. Regulation of RANTES chemokine gene expression requires cooperatively between NF-kB and IFN-regulatory factor transcription factors. J. Immunol. (2000) 164:5352.

Grabovsky V, Dwir O, Alon R. Endothelial chemokines destabilize L-selectin-mediated lymphocyte rolling without inducing selectin shedding. J Biol Chem. (2002) 277(23): 20640–20650

Gunn MD, Tangemann K, Tam C, Cyster JG, Rosen SD, Williams LT. A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Proceedings of the National Academy of Sciences of the United States of America. (1998) 95(1):258-263.

Guo CJ, Douglas SD, Lai JP, Pleasure DE, Li Y, Williams M, Bannerman P, Song L, Ho WZ. Interleukin-1beta stimulates macrophage inflammatory protein-1alpha and -1beta expression in human neuronal cells (NT2-N). J Neurochem. (2003) 84(5):997-1005.

Hehlgans T, Männel DN. The TNF–TNF receptor system. Biol. Chem. (2002)  383: 1581-1585.

Heydtmann M, Adams DH. Understanding selective trafficking of lymphocyte subsets. Gut (2002) 50: 150–152.

Huber A, Kunkel S, Todd RD,  Weiss S. Regulation of transendothelial neutrophil migration by endogenous interleukin-8. Science(1991) 254: 99–102.

Jorgensen I, Lopez JP, Laufer SA, Miao EA. IL-1β, IL-18, and eicosanoids promote neutrophil recruitment to pore-induced intracellular traps following pyroptosis. Eur J Immunol. (2016) 46(12): 2761–2766.

Kujime K, Hashimoto S, Gon Y, Shimizu K, Horie T. p38 mitogenactivated protein kinase and c-jun-NH2-terminal kinase regulate RANTES production by influenza virus-infected human bronchial epithelial cells. J. Immunol. (2000) 164:3222.

Lee SC, Brummet ME, Shahabuddin S, Woodworth TG, Georas SN, Leiferman KM, Gilman SC, Stellato C, Gladue RP, Schleimer RP, Beck LA. Cutaneous injection of human subjects with macrophage inflammatory protein-1 alpha induces significant recruitment of neutrophils and monocytes. J Immunol. (2000) 164: 3392-3401.

Lee PY, Weinstein JS, Nacionales DC, Scumpia PO, Li Y, Butfiloski E, van Rooijen N, Moldawer L, Satoh M, Reeves WH: A novel type I IFN-producing cell subset in murine lupus. J Immunol (2008) 180:5101–5108

Lee PY, Li Y, Kumagai Y, Xu Y,  Weinstein JS, Kellner ES, Nacionales DC, Butfiloski EJ, van Rooijen N, Akira S, Sobel ES, Satoh M, Reeves WH. Type I Interferon Modulates Monocyte Recruitment and Maturation in Chronic Inflammation. Am J Pathol. (2009) 175(5): 2023–2033.

Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol. (2007) 7:678–689.

Lloyd A, Oppenheim J, Kelvin D, Taub D. Chemokines regulate T cell adherence to recombinant adhesion molecules and extracellular matrix proteins. J. Immunol. (1996) 156, 932–938.

Luo BH, Carman CV, Springer TA. Structural basis of integrin regulation and signaling. Annu Rev Immunol. (2007) 25:619–647.

MacEwan DJ. TNF receptor subtype signalling: differences and cellular consequences Cell. Signal. (2002) 14:477-492.

Maruoka S, Hashimoto S, Gon Y, Takeshita I, Horie T. PAFinduced RANTES production by human airway smooth muscle cells requires both p38 MAP kinase and Erk. Am. J. Respir. Crit. Care. Med. (2000) 161:922.

Mellado M, Rodriguez-Frade JM, Mañes S, Martinez AC. Chemokine signaling and functional responses: the role of receptor dimerization and TK pathway activation. Annu Rev Immunol (2001) 19: 397–421.

Miyamoto NG, Medburry PS, Hesselgesser J, Boehlk S, Nelson PJ, Krensky AM, Perez HD. Interleukin-1b induction of the chemokine RANTES promoter in the human astrocytoma line CH235 requires both constitutive and inducible transcription factors. J. Neuroimmunol. (2000) 105:78.

Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 regulates both Th1 and Th2 responses. Annu. Rev. Immunol. (2001) 19: 423–474.

Narumi S, Wyner L, Stoler MH, Tannenbaum CS, Hamilton TA. Tissue-specific expression of murine IP-10 mRNA following systemic treatment with interferon g. J Leukoc Biol. (1992) 52:27.

Nikiforou M, Kemp MW, van Gorp RH, Saito M, Newnham JP, Reynaert NL, Janssen LEW, Jobe AH, Kallapur SG, Kramer BW, Wolfs TG. Selective IL-1α exposure to the fetal gut, lung, and chorioamnion/skin causes intestinal inflammatory and developmental changes in fetal sheep. Lab Invest. (2016) 96(1): 69–80.

Okamura H, Kashiwamura S, Tsutsui, H, Yoshimoto T, Nakanishi K. Regulation of interferon-gamma production by IL-12 and IL-18. Curr. Opin. Immunol. (1998)  10: 259–264.

O'Neill LA. The interleukin-1 receptor/Toll-like receptor superfamily: 10 years of progress Immunol. Rev. (2008) 226: 10-18.

Oo YH, Adams DH. The role of chemokines in the recruitment of lymphocytes to the liver.  J Autoimmun. (2010) 34(1): 45–54.

Ortiz BD, Krensky AM, Nelson PJ. Kinetics of transcription factors regulating the RANTES chemokine gene reveal a developmental switch in nuclear events during T-lymphocyte maturation. Mol. Cell. Biol. (1996) 16:202.

Pober JS, Sessa WC. Evolving functions of endothelial cells in inflammation. Nat Rev Immunol. (2007) 7(10): 803–815.

Schall TJ, Jongstra J, Dyer BJ, Jorgenson J, Clayberger C, Davis MM, Krensky AM. A human T cell-specific molecule is a member of a new gene family. J. Immunol.(1988) 141: 1018–1025.

Schall TJ, Bacon K, Toy KJ, Goeddel DV. Selective attraction of monocytes and T lymphocytes of the memory phenotype by cytokine RANTES. Nature (1990)  347: 669–671.

Shields PL, Morland CM, Salmon M, Qin S, Hubscher SG, Adams DH. Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver. J Immunol (1999) 163: 6236–6243.

Springer TA. Traffic signals on endothelium for lymphocyte recirculation and leukocyte emigration. Annu. Rev. Physiol. (1995) 57:827-872.

Sun Y, Zhu D, Wang G, Wang D, Zhou H, Liu X, Jiang M, Liao L, Zhou Z, Hu J. Pro-Inflammatory Cytokine IL-1β Up-Regulates CXC Chemokine Receptor 4 via Notch and ERK Signaling Pathways in Tongue Squamous Cell Carcinoma. PLoS One. (2015) 10(7):e0132677.

Syrbe U, Siveke J, Hamann A. Th1/Th2 subsets: distinct differences in homing and chemokine receptor expression? Springer Semin Immunopathol. (1999) 21: 263-285.

Tanaka Y, Adams DH, Hubscher S, Hirano H, Siebenlist U, Shaw S. T-cell adhesion induced by proteoglycan-immobilized cytokine MIP-1 beta. Nature (1993) 361: 79–82.

Vaddi K, Newton RC. Regulation of monocyte integrin expression by beta-family chemokines. J. Immunol. (1994) 153: 4721–4732.

von Andrian UH, Chambers JD, McEvoy LM, Bargatze RF, Arfors KE, Butcher EC. Two-step model of leukocyte-endothelial cell interaction in inflammation: distinct roles for LECAM-1 and the leukocyte beta 2 integrins in vivo. Proc Natl Acad Sci U S A. (1991) 88:7538–7542.

Weber C, Belge KU, von Hundelshausen P, Draude G, Steppich B, Mack M, Frankenberger M, Weber KS, Ziegler-Heitbrock HW. Differential chemokine receptor expression and function in human monocyte subpopulations. J Leukoc Biol. (2000) 67: 699-704.

Yadav R, Larbi KY, Young RE, Nourshargh S. Migration of leukocytes through the vessel wall and beyond. Thromb Haemost (2003) 90: 598–606.

Yamada T, Fujieda S, Yanagi S, Yamamura H, Inatome R, Yamamoto H, Igawa H, Saito H. IL-1 induced chemokine production through the association of Syk with TNF receptor-associated factor-6 in nasal fibroblast lines. J Immunol. (2001) 167(1):283-8.

Yang CM, Luo SF, Wang CC, Chiu CT, Chien CS, Lin CC, Hsiao LD. Tumor necrosis factor-a- and interleukin-1b-stimulated cell proliferation through activation of mitogen-activated protein kinase in canine tracheal smooth muscle cells. Br. J. Pharmacol. (2000) 130:891.