Cancer is now one of the major causes of death across the globe. The imbalance of cytokine and chemokine secretion has been reported to be involved in cancer development. Meanwhile, CC chemokines have received considerable interest in cancer research. CCR10, as the latest identified CC chemokine receptor (CCR), has been implicated in the recruitment and infiltration of immune cells, especially lymphocytes, into epithelia such as skin via ligation to two ligands, CCL27 and CCL28. Other than homoeostatic function, several mechanisms have been shown to dysregulate CCR10/CCL27–CCL28 expression in the tumour microenvironment. As such, these receptors and ligands mediate T-cell trafficking in the tumour microenvironment. Depending on the types of lymphocytes recruited, CCR10/CCL27–CCL28 interaction has been shown to play conflicting roles in cancer development. If they were T helper and cytotoxic T cells and natural killer cells, the role of this axis would be tumour-suppressive. In contrast, if CCR10/CCL27–CCL28 recruited regulatory T cells, cancer-associated fibroblasts or myeloid-derived suppressor cells, it would lead to tumour progression. In addition to the trafficking of lymphocytes and immune cells, CCR10 also leads to the migration of tumour cells or endothelial cells (called angiogenesis and lymphangiogenesis) to promote tumour metastasis. Furthermore, CCR10 signalling triggers tumour-promoting signalling such as PI3K/AKT and mitogen-activated protein kinase/extracellular signal-regulated kinase, resulting in tumour cell growth. Since CCR10/CCL27–CCL28 is dysregulated in the tumour tissues, it is suggested that analysis and measurement of them might predict tumour development. Finally, it is hoped using therapeutic approaches based on this axis might increase our knowledge to overcome tumour progression.

Today, cancer is one of the leading causes of death worldwide. Lately, cytokine and chemokine imbalances have gained attention amongst different involved pathways in cancer development and attracted much consideration in cancer research. CXCL16, as a member of the CXC subgroup of chemokines, has been attributed to be responsible for immune cell infiltration into the tumour microenvironment. The aberrant expression of CXCL16 has been observed in various cancers. This chemokine has been shown to play a conflicting role in tumour development through inducing pro-inflammatory conditions. The infiltration of various immune and non-immune cells such as lymphocytes, cancer-associated fibroblasts and myeloid-derived suppressor cells by CXCL16 into the tumour microenvironment has complicated the tumour fate. Given this diverse role of CXCL16 in cancer, a better understanding of its function might build-up our knowledge about tumour biology. Hence, this study aimed to review the impact of CXCL16 in cancer and explored its therapeutic application. Consideration of these findings might provide opportunities to achieve novel approaches in cancer treatment and its prognosis.

Protists are a diverse collection of eukaryotic organisms that account for a significant global infection burden. Often, the immune responses mounted against these parasites cause excessive inflammation and therefore pathology in the host. Elucidating the mechanisms of both protective and harmful immune responses is complex, and often relies of the use of animal models. In any immune response, leucocyte trafficking to the site of infection, or inflammation, is paramount, and this involves the production of chemokines, small chemotactic cytokines of approximately 8–10 kDa in size, which bind to specific chemokine receptors to induce leucocyte movement. Herein, the scientific literature investigating the role of chemokines in the propagation of immune responses against key protist infections will be reviewed, focussing on Plasmodium species, Toxoplasma gondii, Leishmania species and Cryptosporidium species. Interestingly, many studies find that chemokines can in fact, promote parasite survival in the host, by drawing in leucocytes for spread and further replication. Recent developments in drug targeting against chemokine receptors highlights the need for further understanding of the role played by these proteins and their receptors in many different diseases.

The neuropeptide calcitonin gene-related peptide (CGRP) is known to play a pro-nociceptive role after peripheral nerve injury upon its release from primary afferent neurons in preclinical models of neuropathic pain. We previously demonstrated a critical role for spinal cord microglial CD40 in the development of spinal nerve L5 transection (L5Tx)-induced mechanical hypersensitivity. Herein, we investigated whether CGRP is involved in the CD40-mediated behavioral hypersensitivity. First, L5Tx was found to significantly induce CGRP expression in wild-type (WT) mice up to 14 days post-L5Tx. This increase in CGRP expression was reduced in CD40 knockout (KO) mice at day 14 post-L5Tx. Intrathecal injection of the CGRP antagonist CGRP8–37 significantly blocked L5Tx-induced mechanical hypersensitivity. In vitro, CGRP induced glial IL-6 and CCL2 production, and CD40 stimulation added to the effects of CGRP in neonatal glia. Further, there was decreased CCL2 production in CD40 KO mice compared to WT mice 21 days post-L5Tx. However, CGRP8–37 did not significantly affect spinal cord CCL2 production following L5Tx in WT mice. Altogether, these data suggest that CD40 contributes to the maintenance of behavioral hypersensitivity following peripheral nerve injury in part through two distinct pathways, the enhancement of CGRP expression and spinal cord CCL2 production.

Neurological involvement following trypanosome infection has been recognised for over a century. However, there are still many unanswered questions concerning the mechanisms used by the parasite to gain entry to the CNS and the pathogenesis of the resulting neuroinflammatory reaction. There is a paucity of material from human cases of the disease therefore the majority of current research relies on the use of animal models of trypanosome infection. This review reports contemporary knowledge, from both animal models and human samples, regarding parasite invasion of the CNS and the neuropathological changes that accompany trypanosome infection and disease progression. The effects of trypanosomes on the blood-brain barrier are discussed and possible key molecules in parasite penetration of the barrier highlighted. Changes in the balance of CNS cytokines and chemokines are also described. The article closes by summarising the effects of trypanosome infection on the circadian sleep-wake cycle, and sleep structure, in relation to neuroinflammation and parasite location within the CNS. Although a great deal of progress has been made in recent years, the advent and application of sophisticated analysis techniques, to decipher the complexities of HAT pathogenesis, herald an exciting and rewarding period for advances in trypanosome research.

A strong causal link between increased adipose tissue mass and insulin resistance in tissues such as liver and skeletal muscle exists in obesity-related disorders such as type 2 diabetes. Increased adipose tissue mass in obese patients and patients with diabetes is associated with altered secretion of adipokines, which also includes chemotactic proteins. Adipose tissue releases a wide range of chemotactic proteins including many chemokines and chemerin, which are interesting targets for adipose tissue biology and for biomedical research in obesity and obesity-related diseases. This class of adipokines may be directly linked to a chronic state of low-grade inflammation and macrophage infiltration in adipose tissue, a concept intensively studied in adipose tissue biology in recent years. The inflammatory state of adipose tissue in obese patients may be the most important factor linking increased adipose tissue mass to insulin resistance. Furthermore, chemoattractant adipokines may play an important role in this situation, as many of these proteins possess biological activity beyond the recruitment of immune cells including effects on adipogenesis and glucose homeostasis in insulin-sensitive tissues. The present review provides a summary of experimental evidence of the role of adipose tissue-derived chemotactic cytokines and their function in insulin resistance in vivo and in vitro.

The roles of the pro-adipogenic ligands of the transcription factor Peroxisome Proliferator Activated Receptor gamma (PPARG) in regulating innate immune responses in bovine mammary epithelial cells (bMEC) were investigated using quantitative real-time PCR. The analyses revealed that 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) enhanced the expression of Interleukin 8 (IL-8) and Chemokine (C-X-C motif) ligand 6 (CXCL6) in these cells in a dose-dependent manner. 15d-PGJ2 also induced the expression of transcripts encoding proteins involved in oxidative stress, including Ferritin heavy chain and Superoxide dismutase 1, as well as substantial microfilament reorganization. In contrast, synthetic PPARG agonists displayed a different and much smaller range of effects on the cells, causing down-regulation of Interleukin 1-beta, Interleukin 6 and IL-8 and increased expression of Chemokine (C-C motif) ligand 2 (CCL2) and Tumour necrosis factor alpha (TNFα). In an independent analysis, the cells were pre-incubated with PPARG agonists followed by lipopolysaccharide stimulation. This study revealed that troglitazone increased the responsiveness of the cells to lipopolysaccharide resulting in up-regulation of Interleukin 1-beta, TNFα, IL-8, CCL2 and CXCL6 while 15d-PGJ2 caused down-regulation of TNFα, CCL2 and CXCL6. These findings are relevant to understanding the anti-inflammatory potential of the PPARG ligands and underline different mechanisms of action of 15d-PGJ2 and troglitazone in bMEC. Furthermore, the present results demonstrate that the generation of pro-inflammatory mediators can be modulated by currently available therapeutic agents and may therefore be of value in the treatment of mastitis in ruminants.

Ticks are obligatory blood-feeding arthropods that secrete various immunomodulatory molecules to antagonize host inflammatory and immune responses. Cytokines play an important role in regulating these responses. We investigated the extent to which ticks interact with the sophisticated cytokine network by comparing the effect of salivary gland extracts (SGE) of 3 ixodid tick species, Dermacentor reticulatus, Amblyomma variegatum and Ixodes ricinus, all of which are important vectors of tick-borne pathogens. Using specific ELISAs, anti-cytokine activity was demonstrated with 7 cytokines: IL-8, MCP-1, MIP-1α, RANTES, eotaxin, IL-2 and IL-4. The results varied between species, and between adult males and females of the same species. Relatively high activity levels were detected in saliva of female D. reticulatus, confirming that the observed anti-cytokine activities are an integral part of tick saliva secreted into the host. Results with fractionated SGE indicated that from 2 to 6 putative cytokine binding molecules are produced, depending on species and sex. Binding ability of SGE molecules was verified by cross-linking with radio-isotope labelled MIP-1α. By targeting different cytokines, ixodid ticks can manipulate the cytokine network, which will greatly facilitate blood-feeding and provide a gateway for tick-borne pathogens that helps explain why ticks are such efficient and effective disease vectors.

Inflammatory responses occur within tissue microenvironments, with functional contributions from both haematopoietic (lymphocytic) cells and stromal cells (including macrophages and fibroblasts). These environments are complex – a compound of many different cell types at different stages of activation and differentiation. Traditional models of inflammatory disease highlight the role of antigen-specific lymphocyte responses and attempt to identify causative agents. However, recent studies have indicated the importance of tissue microenvironments and the innate immune response in perpetuating the inflammatory process. The prominent role of stromal cells in the generation and maintenance of these environments has begun to challenge the primacy of the lymphocyte in regulating chronic inflammatory processes. Sensible enquiries into factors regulating the persistence of inflammatory disease necessitate an understanding of the mechanisms regulating tissue homeostasis and remodelling during inflammation. This article highlights recent insights into the factors regulating dynamic aspects of inflammation, focusing particularly on mononuclear cell infiltrates, their interactions with stromal cells in tissues and the relevance of these interactions to existing and possible future therapies. A key feature of current research has been a growing appreciation that disordered spatial and temporal interactions between infiltrating immune cells and resident stromal cells lie at the heart of disease persistence.

Chemokines are small, chemotactic cytokines that direct migration of leukocytes, activate inflammatory responses and participate in many other pleiotropic functions, including regulation of tumour growth. Chemokines modulate tumour behaviour by three important mechanisms: regulation of tumour-associated angiogenesis, activation of a host tumour-specific immunological response, and direct stimulation of tumour cell proliferation in an autocrine fashion. All of these mechanisms are promising points of cancer intervention, and preclinical mouse models suggest that chemokine antagonists and agonists could become important in the development of new anticancer therapies.

We have modeled the structure of human lymphotactin (hLpnt), by homology modeling and molecular dynamics simulations. This chemokine is unique in having a single disulfide bond and a long C-terminal tail. Because other structural classes of chemokines have two pairs of Cys residues, compared to one in Lpnt, and because it has been shown that both disulfide bonds are required for stability and function, the question arises how the Lpnt maintains its structural integrity. The initial structure of hLpnt was constructed by homology modeling. The first 63 residues in the monomer of hLpnt were modeled using the structure of the human CC chemokine, RANTES, whose sequence appeared most similar. The structure of the long C-terminal tail, missing in RANTES, was taken from the human muscle fatty-acid binding protein. In a Protein Data Bank search, this protein was found to contain a sequence that was most homologous to the long tail. Consequently, the modeled hLpnt C-terminal tail consisted of both α-helical and β-motifs. The complete model of the hLpnt monomer consisted of two α-helices located above the five-stranded β-sheet. Molecular dynamics simulations of the solvated initial model have indicated that the stability of the predicted fold is related to the geometry of Pro78. The five-stranded β-sheet appeared to be preserved only when Pro78 was modeled in the cis conformation. Simulations were also performed both for the C-terminal truncated forms of the hLpnt that contained one or two (CC chemokine-like) disulfide bonds, and for the chicken Lpnt (cLpnt). Our MD simulations indicated that the turn region (T30–G34) in hLpnt is important for the interactions with the receptor, and that the long C-terminal region stabilizes both the turn (T30–G34) and the five-stranded β-sheet. The major conclusion from our theoretical studies is that the lack of one disulfide bond and the extension of the C-terminus in hLptn are mutually complementary. It is very likely that removal of two Cys residues sufficiently destabilizes the structure of a chemokine molecule, particularly the core β-sheet, to abolish its biological function. However, this situation is rectified by the long C-terminal segment. The role of this long region is most likely to stabilize the first β-turn region and α-helix H1, explaining how this chemokine can function with a single disulfide bond.

We report the solution structure of the chemotactic cytokine (chemokine) vMIP-II. This protein has unique biological activities in that it blocks infection by several different human immunodeficiency virus type 1 (HIV-1) strains. This occurs because vMIP-II binds to a wide range of chemokine receptors, some of which are used by HIV to gain cell entry. vMIP-II is a monomeric protein, unlike most members of the chemokine family, and its structure consists of a disordered N-terminus, followed by a helical turn (Gln25–Leu27), which leads into the first strand of a three-stranded antiparallel β-sheet (Ser29–Thr34; Gly42–Thr47; Gln52–Asp56). Following the sheet is a C-terminal α-helix, which extends from residue Asp60 until Gln68. The final five residues beyond the C-terminal helix (Pro70–Arg74) are in an extended conformation, but several of these C-terminal residues contact the first β-strand. The structure of vMIP-II is compared to other chemokines that also block infection by HIV-1, and the structural basis of its lack of ability to form a dimer is discussed.