Interleukin-8 in gastrointestinal inflammation and malignancy: induction and clinical consequences

Figures & data

Table 1 CXCL chemokine family related to CXCL8

CXC family (human)	Alternative names	Chromosome	Mouse ortholog	Alternative names	Receptor(s)	ELR+	References
CXCL1	GROα	4q13.3	CXCL1	GRO/KC	CXCR1, CXCR2	Yes	303,304
CXCL2	GROβ	4q13.3	CXCL2	MIP-2	CXCR2	Yes	303,304
CXCL3	GROγ	4q13.3	GM1960	Dcip1	CXCR2	Yes	303,304
CXCL4	PF4	4q13.3	CXCL4	PF4	CXCR3b	No	303,304
CXCL5	ENA-78	4q13.3	CXCL5	LIX	CXCR2	Yes	303,304
CXCL6	GCP-2	4q13.3			CXCR1, CXCR2	Yes	303,304
CXCL7	NAP-2	4q13.3	CXCL7	Ppbp		Yes	303,304
CXCL8	IL-8	4q13.3			CXCR1, CXCR2	Yes	303,304
CXCL9	MIG	4q21.1	CXCL9	MIG	CXCR3, CXCR3b	No	303,304
CXCL10	IP-10	4q21.1	CXCL10	IP-10	CXCR3, CXCR3b	No	303,304

Table 2 ELR+ CXCL chemokine family members related to CXCL8

CXC family (human)	Alternative names	Chromosome	Mouse ortholog	Alternative names	Receptor(s)	References
CXCL1	GROα	4q13.3	CXCL1	GRO/KC	CXCR1, CXCR2	303,304
CXCL2	GROβ	4q13.3	CXCL2	MIP-2	CXCR2	303,304
CXCL3	GROγ	4q13.3	GM1960	Dcip1	CXCR2	303,304
CXCL5	ENA-78	4q13.3	CXCL5	LIX	CXCR2	303,304
CXCL6	GCP-2	4q13.3			CXCR1, CXCR2	303,304
CXCL7	NAP-2	4q13.3	CXCL7	Ppbp		303,304
CXCL8	IL-8	4q13.3			CXCR1, CXCR2	303,304

Figure 1 An overview of CXCL8 gene regulation and the signalling cascades downstream of CXCL8-mediated CXCR1/2 activation.

Notes: (A) Phosphorylation of IκBα and JAK proteins following receptor activation (eg, IL-1R, TLRs, etc) allows for the nuclear translocation of transcription factors and the subsequent expression of target genes, such as CXCL8.^39–50 (B) The effects of CXCL8-activated signalling cascades on the pathogenesis of inflammatory bowel diseases and tumorigenesis (see Tables 3 and 4).
Abbreviations: IL-1R, interleukin-1 receptor; TLRs, toll-like receptors; PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns.

Figure 2 CXC ELR+ chemokines in mice.

Table 3 The role of CXCL8 in promoting inflammation

Function	Mechanism(s)	References
Increased tissue recruitment of PMNs	– Enhanced egression of PMNs from the bone marrow – Extravasation of PMNs from the vasculature through the promotion of firm adhesion to the endothelium via inside-out signaling to PMN integrins – Induction of PMN chemotaxis toward infectious/inflammatory sites within tissues as an intermediate chemoattractant	151–169
Enhanced respiratory burst in neutrophils	– Priming of NADPH-oxidase activity thorough the upregulation of fMLF receptors, increased intracellular calcium concentrations, and the phosphorylation of its p47^phox and p67^phox subunits	186–192
Enhanced PMN degranulation	– Induction of degranulation through the activation of CXCRI and CXCR2 on PMNs	185,213–215
Preclinical studies and early clinical trials with CXCL8, CXCR1/2 inhibitors	– CXCR2 inhibitors used in colorectal cancer models, arthritis, IBD (DSS), and clinical trials for RA, COPD, asthma, and psoriasis	298–312

Abbreviations: PMNs, polymorphonuclear cells; NADPH, nicotinamide adenine dinucleotide phosphate; fMLF, formyl-methionyl-leucyl phenylalanine; IBD, inflammatory bowel disease; DSS, dextran sulfate sodium; RA, rheumatoid arthritis.

Table 4 Role of CXCL8 in promoting tumorigenesis and malignancy in gastric and intestinal carcinomas

Function	Mechanism(s)	References
Increased angiogenesis	– Recruitment of inflammatory cells that express proangiogenic factors – Induction of MMP-2, MMP-9, and VEGF – Induction of endothelial cell proliferation and capillary tube rearrangement – Inhibition of endothelial cell apoptosis through the upregulation of antiapoptotic proteins (ie, Bcl-XL, Bcl-XS)	145,240,246, 249,254–261
Increased epithelial-to-mesenchymal transition	– Increased expression of EGFR, MMP-9, and VEGF by gastric and intestinal epithelial cells – Decreased expression of E-cadherin by gastric and intestinal epithelial cells – Enhanced migratory and invasive properties in gastric and intestinal epithelial cells	77,257
Enhanced recruitment of myeloid-derived suppressor cells to the tumor microenvironment	– Suppression of antitumor immune responses – Increased angiogenesis	84,278
Enhanced migration and invasion of cancer cells	– Possibly due to increased FAK and Src phosphorylation – Noted in prostate, melanoma, colon, and gastric cancers	78,261
Resistance to chemotherapy	– Decreased sensitivity to oxaliplatin due to enhanced CXCL8-dependent NF-κΒ signaling, triggering the upregulation of antiapoptotic proteins	261,267,281,285,291
Oncogenic mutations or loss of tumor suppressor genes can increase CXCL8 signaling Inflammation/tumor environment can increase CXCL8-CXCRI/2 signaling	– Activating mutations in Ras-GTPase or loss of functional PTEN can increase CXCL8 signaling as can Wnt/β-catenin – Hypoxia, acidosis, altered glucose metabolism, TNFa, and IL-Iβ – CXCL8-CXCRI/2 signaling can also activate numerous transcription factors, including NF-κΒ, AP-I, β-catenin/TCF, STAT3, and HIF	261,267,292,298 261,300
Neutralizing antibodies or other inhibitors of CXCL8-CXCRI/2 reduce tumor burden	– Numerous animal studies show efficacy of neutralizing antibodies and small molecule inhibitors (several are now in clinical trials) – Reduction in angiogenesis, cell proliferation, and cancer-associated inflammation	261

Abbreviations: MMP, matrix metalloproteinase; VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor; GTPase, guanosine triphosphatase.

Table 5 CXCR1/2 small molecule antagonists in development for inflammation and neoplasia

Receptor	Antagonist	Preclinical	Clinical trials
CXCRI	Reparixin	Breast cancer xenographs	Breast cancer, islet transplant
CXCRI/2	DF2162	Breast cancer xenographs	Breast cancer, islet transplant
CXCR2	SCH527123	Colorectal xenographs	Ozone-induced lung inflammation, COPD, asthma
CXCR2	SB225002	Colitis	Ozone-induced lung inflammation, COPD, CF, UC
CXCR2	SB656933	Colitis	Ozone-induced lung inflammation, COPD, CF, UC
CXCR2	AZD8309		RA, COPD, asthma, bronchiectasis
CXCR2	AZD5069		RA, COPD, asthma, bronchiectasis

Note: See Campbell et al for further details.²⁶²

Abbreviations: CF, cystic fibrosis; UC, ulcerative colitis; RA, rheumatoid arthritis.

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