Chemokines in health and disease

doi:10.1016/j.yexcr.2011.01.005

Experimental Cell Research

Volume 317, Issue 5, 10 March 2011, Pages 575-589

https://doi.org/10.1016/j.yexcr.2011.01.005 Get rights and content

Abstract

Chemokines and their receptors play a key role in development and homeostasis as well as in the pathogenesis of tumors and autoimmune diseases. Chemokines are involved in the implantation of the early conceptus, the migration of subsets of cells during embryonic development, and the overall growth of the embryo. Chemokines also have an important role in the development and maintenance of innate and adaptive immunity. In addition, they play a significant role in wound healing and angiogenesis. When the physiological role of chemokines is subverted or chronically amplified, disease often follows. Chemokines are involved in the pathobiology of chronic inflammation, tumorigenesis and metastasis, as well as autoimmune diseases. This article reviews the role of chemokines and their receptors in normal and disease processes and the potential for using chemokine antagonists for appropriate targeted therapy.

Section snippets

Chemokine receptor signaling, receptor dimerization and chemotaxis

Chemokine receptors are seven transmembrane G-protein coupled receptors (GPCRs) that bind chemokine ligands with high affinity to activate the heterotrimeric Gα_iβγ. Τhe exchange of GDP for GTP induces separation of Gα (usually Gα_i) and Gβγ subunits followed by the activation of a series of downstream effectors [3]. A number of adaptor proteins dynamically interact with chemokine GPCRs to facilitate internalization and signal transduction and this dynamic interaction continues during vesicular

Chemokines in inflammation and cancer

Chronic inflammatory conditions have often been associated with the development of cancer. Mantovani and colleagues have proposed that inflammation is the seventh hallmark of cancer as it is a key component of the tumor microenvironment. Inflammation and cancer are connected by: 1) the extrinsic pathway, where chronic inflammatory conditions such as ulcerative colitis may predispose to cancer; 2) the intrinsic pathway where genetic events important for transformation promote the production of

Conclusions

Chemokines play a paramount role in physiology and homeostasis as well as in the pathogenesis of tumors and their metastasis. Based on what is known currently, a multi-pronged anti-tumor therapeutic approach would be beneficial. This includes the reduction or elimination of inflammation, oncogene inactivation, and polarization of the immune cells to Th1 type. A variety of approaches are involved in the reduction or removal of the inflammation. It may be the lowering of stress level, chronic low

Acknowledgments

This work was supported in whole or in part by the National Institutes of Health Grants — CA34590 (A.R.); Specialized Neuroscience Research Program grant U54NS041071-6 under Project 2 (A.R.). This work was also supported by a Senior Research Career Scientist Award from the Department of Veterans Affairs and Ingram Professorship (A. R.).

References (219)

A. Zlotnik et al.
Chemokines: a new classification system and their role in immunity
Immunity
(2000)
D. Raman et al.
Characterization of chemokine receptor CXCR2 interacting proteins using a proteomics approach to define the CXCR2 “chemosynapse”
Meth. Enzymol.
(2009)
D. Sohy et al.
Allosteric transinhibition by specific antagonists in CCR2/CXCR4 heterodimers
J. Biol. Chem.
(2007)
D. Sohy et al.
Hetero-oligomerization of CCR2, CCR5, and CXCR4 and the protean effects of “selective” antagonists
J. Biol. Chem.
(2009)
C. Porcile et al.
Stromal cell-derived factor-1alpha (SDF-1alpha/CXCL12) stimulates ovarian cancer cell growth through the EGF receptor transactivation
Exp. Cell Res.
(2005)
M. Wong et al.
Rantes activates Jak2 and Jak3 to regulate engagement of multiple signaling pathways in T cells
J. Biol. Chem.
(2001)
M.M. Wong et al.
Chemokines: attractive mediators of the immune response
Semin. Immunol.
(2003)
J. Sai et al.
Parallel phosphatidylinositol 3-kinase (PI3K)-dependent and Src-dependent pathways lead to CXCL8-mediated Rac2 activation and chemotaxis
J. Biol. Chem.
(2008)
J. Sai et al.
The IL sequence in the LLKIL motif in CXCR2 is required for full ligand-induced activation of Erk, Akt, and chemotaxis in HL60 cells
J. Biol. Chem.
(2006)
S. Even-Ram et al.
Cell migration in 3D matrix
Curr. Opin. Cell Biol.
(2005)

J.D. Shields et al.

Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling

Cancer Cell

(2007)

K.E. McGrath et al.

Embryonic expression and function of the chemokine SDF-1 and its receptor, CXCR4

Dev. Biol.

(1999)

B. Boldajipour et al.

Control of chemokine-guided cell migration by ligand sequestration

Cell

(2008)

M. Li et al.

Multiple roles of chemokine CXCL12 in the central nervous system: a migration from immunology to neurobiology

Prog. Neurobiol.

(2008)

H.H. Tsai et al.

The chemokine receptor CXCR2 controls positioning of oligodendrocyte precursors in developing spinal cord by arresting their migration

Cell

(2002)

S. Akira et al.

Pathogen recognition and innate immunity

Cell

(2006)

C. Esche et al.

Chemokines: key players in innate and adaptive immunity

J. Invest. Dermatol.

(2005)

W. Weninger et al.

Chemokine regulation of naive T cell traffic in health and disease

Semin. Immunol.

(2003)

R.M. Devalaraja et al.

Delayed wound healing in CXCR2 knockout mice

J. Invest. Dermatol.

(2000)

T. Thuraisingam et al.

MAPKAPK-2 signaling is critical for cutaneous wound healing

J Invest Dermatol

(2010)

R.M. Strieter et al.

CXC chemokines in angiogenesis

Cytokine Growth Factor Rev.

(2005)

R.M. Strieter et al.

The functional role of the ELR motif in CXC chemokine-mediated angiogenesis

J. Biol. Chem.

(1995)

J. Yang et al.

The angiostatic activity of interferon-inducible protein-10/CXCL10 in human melanoma depends on binding to CXCR3 but not to glycosaminoglycan

Mol. Ther.

(2004)

C. Murdoch et al.

Cxc chemokine receptor expression on human endothelial cells

Cytokine

(1999)

J. Heidemann et al.

Angiogenic effects of interleukin 8 (CXCL8) in human intestinal microvascular endothelial cells are mediated by CXCR2

J. Biol. Chem.

(2003)

M. Strasly et al.

CCL16 activates an angiogenic program in vascular endothelial cells

Blood

(2004)

S. Reuter et al.

Oxidative stress, inflammation, and cancer: how are they linked?

Free Radic. Biol. Med.

(2010)

A. Mantovani et al.

The chemokine system in cancer biology and therapy

Cytokine Growth Factor Rev.

(2010)

D. Wang et al.

The role of chemokines in intestinal inflammation and cancer

Curr. Opin. Pharmacol.

(2009)

L. Yang et al.

Abrogation of TGF beta signaling in mammary carcinomas recruits Gr-1⁺CD11b⁺ myeloid cells that promote metastasis

Cancer Cell

(2008)

G. Lazennec et al.

Chemokines and chemokine receptors: new insights into cancer-related inflammation

Trends Mol. Med.

(2010)

D. Raman et al.

Role of chemokines in tumor growth

Cancer Lett.

(2007)

A. Mantovani et al.

Tumor-associated macrophages and the related myeloid-derived suppressor cells as a paradigm of the diversity of macrophage activation

Hum. Immunol.

(2009)

U. Grohmann et al.

Tolerance, DCs and tryptophan: much ado about IDO

Trends Immunol.

(2003)

P.M. Murphy et al.

International Union of Pharmacology. XXII. Nomenclature for chemokine receptors

Pharmacol. Rev.

(2000)

E.R. Neptune et al.

Receptors induce chemotaxis by releasing the betagamma subunit of Gi, not by activating Gq or Gs

Proc. Natl Acad. Sci. USA

(1997)

Neel, N. F. (2008). Regulation of CXC chemokine receptor function through intracellular trafficking and novel...

N.F. Neel et al.

VASP is a CXCR2-interacting protein that regulates CXCR2-mediated polarization and chemotaxis

J. Cell Sci.

(2009)

D. Raman et al.

LIM and SH3 protein-1 modulates CXCR2-mediated cell migration

PLoS ONE

(2010)

A.J. Ridley et al.

Cell migration: integrating signals from front to back

Science

(2003)

C. Porcile et al.

CXCR4 activation induces epidermal growth factor receptor transactivation in an ovarian cancer cell line

Ann. NY Acad. Sci.

(2004)

M. Majka et al.

SDF-1 alone and in co-operation with HGF regulates biology of human cervical carcinoma cells

Folia Histochem. Cytobiol.

(2006)

S.I. Fraley et al.

A distinctive role for focal adhesion proteins in three-dimensional cell motility

Nat. Cell Biol.

(2010)

M. Klemke et al.

An MEK-cofilin signalling module controls migration of human T cells in 3D but not 2D environments

EMBO J.

(2010)

C. Bonvin et al.

A multichamber fluidic device for 3D cultures under interstitial flow with live imaging: development, characterization, and applications

Biotechnol. Bioeng.

(2010)

L.G. Griffith et al.

Capturing complex 3D tissue physiology in vitro

Nat. Rev. Mol. Cell Biol.

(2006)

M.M. Choe et al.

Physiological 3D tissue model of the airway wall and mucosa

Nat. Protoc.

(2006)

U. Haessler et al.

An agarose-based microfluidic platform with a gradient buffer for 3D chemotaxis studies

Biomed. Microdevices

(2009)

J.A. Pedersen et al.

Mechanobiology in the third dimension

Ann. Biomed. Eng.

(2005)

M.C. Poznansky et al.

Efficient generation of human T cells from a tissue-engineered thymic organoid

Nat. Biotechnol.

(2000)

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ReviewChemokines in health and disease

Abstract

Section snippets

Chemokine receptor signaling, receptor dimerization and chemotaxis

Chemokines in inflammation and cancer

Conclusions

Acknowledgments

Immunity

Meth. Enzymol.

J. Biol. Chem.

J. Biol. Chem.

Exp. Cell Res.

J. Biol. Chem.

Semin. Immunol.

J. Biol. Chem.

J. Biol. Chem.

Curr. Opin. Cell Biol.

Cancer Cell

Dev. Biol.

Cell

Prog. Neurobiol.

Cell

Cell

J. Invest. Dermatol.

Semin. Immunol.

J. Invest. Dermatol.

J Invest Dermatol

Cytokine Growth Factor Rev.

J. Biol. Chem.

Mol. Ther.

Cytokine

J. Biol. Chem.

Blood

Free Radic. Biol. Med.

Cytokine Growth Factor Rev.

Curr. Opin. Pharmacol.

Cancer Cell

Trends Mol. Med.

Cancer Lett.

Hum. Immunol.

Trends Immunol.

International Union of Pharmacology. XXII. Nomenclature for chemokine receptors

Pharmacol. Rev.

Receptors induce chemotaxis by releasing the betagamma subunit of Gi, not by activating Gq or Gs

Proc. Natl Acad. Sci. USA

VASP is a CXCR2-interacting protein that regulates CXCR2-mediated polarization and chemotaxis

J. Cell Sci.

LIM and SH3 protein-1 modulates CXCR2-mediated cell migration

PLoS ONE

Cell migration: integrating signals from front to back

Science

CXCR4 activation induces epidermal growth factor receptor transactivation in an ovarian cancer cell line

Ann. NY Acad. Sci.

SDF-1 alone and in co-operation with HGF regulates biology of human cervical carcinoma cells

Folia Histochem. Cytobiol.

A distinctive role for focal adhesion proteins in three-dimensional cell motility

Nat. Cell Biol.

An MEK-cofilin signalling module controls migration of human T cells in 3D but not 2D environments

EMBO J.

A multichamber fluidic device for 3D cultures under interstitial flow with live imaging: development, characterization, and applications

Biotechnol. Bioeng.

Capturing complex 3D tissue physiology in vitro

Nat. Rev. Mol. Cell Biol.

Physiological 3D tissue model of the airway wall and mucosa

Nat. Protoc.

An agarose-based microfluidic platform with a gradient buffer for 3D chemotaxis studies

Biomed. Microdevices

Mechanobiology in the third dimension

Ann. Biomed. Eng.

Efficient generation of human T cells from a tissue-engineered thymic organoid

Nat. Biotechnol.

Review
Chemokines in health and disease