"The good, the bad, and the ugly." The role of chemokines in models of human disease

• Published in: The Journal of immunology (1950) Vol. 156; no. 10; pp. 3583 - 3586
• Main Authors: Strieter, R M, Standiford, T J, Huffnagle, G B, Colletti, L M, Lukacs, N W, Kunkel, S L
• Format: Journal Article
• Language: English
• Published: United States 15-05-1996
• Subjects: Animals; Arthritis - immunology; Chemokines - immunology; Disease Models, Animal; Humans; Hypersensitivity - immunology; Hypersensitivity - pathology; Models, Immunological; Reperfusion Injury - immunology
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.156.10.3583

The salient feature of a variety of inflammatory conditions, such as infection, allergic disorders, autoimmune diseases, or ischemia /reperfusion injury is the association of infiltrating leukocytes. These extravasating leukocytes often contributes to the pathogenesis of the underlying disease. However, it should be appreciated that leukocyte recruitment is also critical for host defense, leading to clearance of the inciting factor(s), i.e., infection. While the events of leukocyte trafficking may appear intuitive, it has taken over 150 years of research to elucidate the molecular and cellular steps involved in the process of leukocyte migration. The maintenance of leukocyte recruitment during inflammation requires intercellular communication between infiltrating leukocytes and the endothelium, resident stromal and parenchyma cells. These events are mediated via the generation of early response cytokines, e.g., IL-1 and TNF- alpha , the expression of cell-surface adhesion molecules, and the production of chemotactic molecules, such as chemokines. The human CXC, CC, and C chemokine family of chemotactic cytokines are three closely related polypeptide families that behave, in general, as potent chemotactic factors for either neutrophils, mononuclear cells, or lymphocytes, respectively. These cytokines in their monomeric form range from 7 to 10 kDa and are characteristically basic heparin-binding proteins. The chemokines display three highly conserved cysteine amino acid residues: the CXC chemokine family has the first two NH sub(2)-terminal cysteines separated by one nonconserved amino acid residue, the CXC cysteine motif; the CC chemokine family has the first two NH sub(2)-terminal cysteines in juxtaposition, the CC cysteine motif; and the C chemokine has one lone NH sub(2)-terminal cysteine amino acid, the C cysteine motif. Interestingly, CXC chemokines are clustered on human chromosome 4 and exhibit from 20 to 50% homology on the amino acid level, CC chemokines are clustered on human chromosome 17 and exhibit from 28 to 45% homology on the amino acid level, and the one C chemokine, lymphotactin, is located on human chromosome 1. There is approximately 20 to 40% homology among the members of the three chemokine families. The murine homologues of the human CXC chemokines are KC, macrophage inflammatory protein-2 (MIP-2), crg-2, and MIG and are structurally homologous to human GRO- alpha , GRO- beta /GRO- gamma , interferon- gamma -inducible protein (IP-10), and MIG, respectively. No murine or rat structural homologue exists for human IL-8. The murine CC and C chemokines, in general, are known by the same names as their human counterparts, with the exception of T cell activation gene (TCA-3), which is structurally homologous with I-309. Chemokines have been found to be produced by an array of cells including monocytes, alveolar macrophages, neutrophils, platelets, eosinophils, mast cells, T lymphocytes, NK cells, keratinocytes, mesangial cells, epithelial cells, hepatocytes, fibroblasts, smooth muscle cells, mesothelial cells, and endothelial cells. These cells can produce chemokines in response to a variety of factors, including viruses, bacterial products, IL-1, TNF, C5a, LTB4, and IFNs. The production of chemokines by both immune and nonimmune cells support the contention that these cytokines may play a pivotal role in orchestrating inflammation. To illustrate the importance of chemokines during the pathogenesis of inflammation, we will focus our discussion in this commentary on the role of CXC and CC chemokines in the elicitation of leukocytes in animal models of inflammation. These models are relevant to human disease and demonstrate that the production of chemokines can be either beneficial or detrimental to the host.