***************************************************** * Small cytokines (intercrine/chemokine) signatures * ***************************************************** Many low-molecular weight factors secreted by cells including fibroblasts, macrophages and endothelial cells, in response to a variety of stimuli such as growth factors, interferons, viral transformation and bacterial products, are structurally related [1,2,3]. Most members of this family of proteins seem to have mitogenic, chemotactic or inflammatory activities. These small cytokines are also called intercrines or chemokines. They are cationic proteins of 70 to 100 amino acid residues that share four conserved cysteine residues involved in two disulfide bonds, as shown in the following schematic representation: +------------------------------------+ | | xxxxxxxxxxxxxxxxxxxxxxCxCxxxxxxxxxxxxxxxxxxxxxxxCxxxxxxxxxxxxCxxxxx | | +-------------------------+ 'C': conserved cysteine involved in a disulfide bond. These proteins can be sorted into two groups based on the spacing of the two amino-terminal cysteines. In the first group, the two cysteines are separated by a single residue (C-x-C), while in the second group, they are adjacent (C-C). The 'C-x-C' group is currently known to consist of the following proteins: - Platelet factor 4 (PF4), a protein released from platelet alpha-granules as a complex with a proteoglycan molecule. PF4 neutralizes the anticoagulant effect of heparin because it binds more strongly to heparin than to the chondroitin-4-sulfate chains of the carrier molecule. PF4 is chemotactic for neutrophils and monocytes. - Platelet basic protein (PBP), which is the precursor of two active peptides: connective-tissue activating peptide III (CTAP III) (also known as low- affinity platelet factor IV (LA-PF4)) and beta-thromboglobulin. CTAP-III is a growth factor that stimulates a variety of specific metabolic and cellular activities. - Interleukin-8 (IL-8), a monokine which is released from monocytes by an inflammatory response and which is selectively chemotactic for neutrophils. IL-8 is also known as Monocyte-Derived Neutrophil Chemotactic Factor (MDNCF), or as Neutrophil Activating Protein 1 (NAP-1). - Melanoma growth stimulatory activity protein (MGSA), a growth factor with potent mitogenic activity. MGSA is also known as Neutrophil Activating Protein 3 (NAP-3) or as 'gro', as KC or N51 in mouse and as CICN in rat. - Macrophage inflammatory protein 2 (MIP-2), an extremely potent chemotactic agent for polymorphonuclear leukocytes. - Mouse Mig (m119), a gamma-interferon induced protein that may be a cytokine affecting the growth, movement or activation state of cells that participate in immune and inflammatory response. - Chicken 9E3 (or pCEF-4), a protein expressed constitutively in Rous Sarcoma virus (RSV) infected cells and which may be an autocrine factor that promotes the growth of fibroblasts. - Pig alveolar macrophage chemotactic factors I and I (AMCF-I and -II). - IP10, a gamma-interferon induced protein. The 'C-C' group is currently known to consist of the following proteins: - Monocyte chemotactic protein 1 (MCP-1). MCP-1 is a chemoattractant for monocytes which also increases their anti-tumor activity. MCP-1 is also known as monocyte chemotactic and activating factor (MCAF) or as JE in rodents. - Monocyte chemotactic protein 2 (MCP-2). - Monocyte chemotactic protein 3 (MCP-3). - Macrophage inflammatory protein 1 alpha (MIP-1-alpha), a monokine with inflammatory and chemokinetic properties. MIP-1-alpha is also known as SIS- alpha, TY-5 or L2G25B and, in Human, as PAT 464.1 or GOS19-1. - Macrophage inflammatory protein 1 beta (MIP-1-beta). Also known as SIS- gamma, H400 and, in Human, as ACT-2 or PAT 744. - LD78 beta (also known as PAT 464.2 or GOS19-2). - SIS-delta (also known as RANTES). - SIS-epsilon (p500). - Guinea pig eotaxin, a chemotactic protein that promotes the accumulation of eosinophils. - I-309 (also known, in mouse, as TCA3), a cytokine that is chemotactic for monocytes but not for neutrophils. - Mouse protein C10. - Mouse protein Marc/FIC. For each of the two groups of proteins, we have developed a signature pattern spanning the region that includes the four conserved cysteines. -Consensus pattern: C-x-C-[LIVM]-x(5,6)-[LIVMFY]-x(2)-[RK]-x-[LIVM]-x(2)- [LIVM]-x(5)-[SAG]-x(2)-C-x(3)-[EQ]-[LIVM](2)-x(9,10)-C-L- [DN] [The four C's are involved in disulfide bonds] -Sequences known to belong to this class detected by the pattern: ALL C-x-C. -Other sequence(s) detected in SWISS-PROT: NONE. -Consensus pattern: C-C-[LIVMFY]-x(5,6)-[LIVM]-x(4)-[LIVMF]-x(2)-Y-x(2,3)- [GSTN](2)-x(1,2)-C-x(3,4)-[SAG]-[LIVM](2)-F-x(5)-[RKTM]- x(2)-C [The four C's are involved in disulfide bonds] -Sequences known to belong to this class detected by the pattern: ALL C-C. -Other sequence(s) detected in SWISS-PROT: NONE. -Last update: June 1994 / Text revised. [ 1] Oppenheim J.J., Zachariae C.O.C., Mukaida N., Matsushima K. Annu. Rev. Immunol. 9:617-68(1991). [ 2] Stoeckle M.Y., Barker K.A. New Biol. 2:313-323(1990). [ 3] Wolpe S.D., Cerami A. FASEB J. 3:2565-2573(1989).