The
chemokine (C-X-C motif) ligand 1
(CXCL1) is a small peptide belonging to the CXC
chemokine
family that acts as a chemoattractant for several immune cells, especially
neutrophils
[3]
[4]
or other non-hematopoietic cells to the site of injury or infection and plays an important role in regulation of immune and inflammatory responses. It was previously called GRO1 oncogene, GROα, neutrophil-activating protein 3 (NAP-3) and melanoma growth stimulating activity, alpha (MGSA-α). CXCL1 was first cloned from a cDNA library of genes induced by platelet-derived growth factor (PDGF) stimulation of BALB/c-3T3 murine embryonic fibroblasts and named "KC" for its location in the nitrocellulose colony hybridization assay.
[5]
This designation is sometimes erroneously believed to be an acronym and defined as "keratinocytes-derived chemokine". Rat CXCL1 was first reported when NRK-52E (normal rat kidney-52E) cells were stimulated with interleukin-1β (IL-1β) and lipopolysaccharide (LPS) to generate a cytokine that was chemotactic for rat neutrophils, cytokine-induced neutrophil chemoattractant (CINC).
[6]
In humans, this protein is encoded by the
gene
Cxcl1
[7]
and is located on human
chromosome 4
among genes for other CXC chemokines.
[8]
Structure and expression
CXCL1 exists as both monomer and dimer and both forms are able to bind chemokine receptor
CXCR2
.
[9]
However, CXCL1 chemokine is able to dimerize only at higher (micromolar) concentrations and its concentrations are only nanomolar or picomolar upon normal conditions, which means that the form of WT CXCL1 is more likely monomeric while dimeric CXCL1 is present only during infection or injury. CXCL1 monomer consists of three antiparallel
β-strands
followed by C- terminal
α-helix
and this α-helix together with the first β-strand are involved in forming a dimeric globular structure.
[10]
CXCL1 has a potentially similar role as
interleukin-8
(IL-8/CXCL8). After binding to its receptor CXCR2, CXCL1 activates phosphatidylinositol-4,5-bisphosphate 3-kinase-γ (PI3Kγ)/Akt, MAP kinases such as ERK1/ERK2 or phospholipase-β (PLCβ) signaling pathways. CXCL1 is expressed at higher levels during inflammatory responses thus contributing to the process of inflammation.
[14]
CXCL1 is also involved in the processes of
wound healing
and
tumorigenesis
.
[15]
[16]
[17]
Role in cancer
CXCL1 has a role in angiogenesis and arteriogenesis
[18]
and thus has been shown to act in the process of tumor progression. The role of CXCL1 was described by several studies in the development of various tumors, such as breast cancer, gastric and colorectal carcinoma or lung cancer.
[19]
[20]
[21]
Also, CXCL1 is secreted by human
melanoma
cells, has
mitogenic
properties and is implicated in melanoma
pathogenesis
.
[22]
[23]
[24]
Role in nervous system and sensitization
CXCL1 plays a role in spinal cord development by inhibiting the migration of oligodendrocyte precursors.
[9]
CXCR2 receptor for CXCL1 is expressed in the brain and spinal cord by
neurons
and oligodendrocytes and during CNS pathologies such as Alzheimer's disease,
multiple sclerosis
and brain injury also by
microglia
. An initial study in mice showed evidence that CXCL1 decreased the severity of multiple sclerosis and may offer a neuro-protective function.
[25]
On the other hand, on the periphery, CXCL1 contributes to the release of
prostaglandins
and thus causes increased sensitivity to pain and drives nociceptive sensitization via recruitment of neutrophils to the tissue. Phosphorylation of ERK1/ERK2 kinases and activation of
NMDA receptors
leads to transcription of genes inducing chronic pain, such as
c-Fos
or
cyclooxygenase
-2 (COX-2).
[14]
↑
Watanabe K, Kinoshita S, Nakagawa H (June 1989). "Purification and characterization of cytokine-induced neutrophil chemoattractant produced by epithelioid cell line of normal rat kidney (NRK-52E cell)".
Biochemical and Biophysical Research Communications
.
161
(3): 1093–1099.
doi
:
10.1016/0006-291X(89)91355-7
.
PMID
2662972
.
↑
Richmond A, Thomas HG (February 1988). "Melanoma growth stimulatory activity: isolation from human melanoma tumors and characterization of tissue distribution".
Journal of Cellular Biochemistry
.
36
(2): 185–198.
doi
:
10.1002/jcb.240360209
.
PMID
3356754
.
S2CID
10674236
.