Human Mig chemokine: biochemical and functional characterization.

Abstract

SummaryMig is a chemokine of the CXC subfamily that was discovered by differential screening of a cDNA library prepared from lymphokine-activated macrophages. The mig gene is inducible in macrophages and in other cells in response to interferon (IFN)-% We have transfected Chinese hamster ovary (CHO) cells with cDNA encoding human Mig and we have derived CHO cell lines from which we have purified recombinant human Mig (rHuMig). rHuMig induced the transient elevation of [Ca2+]i in human tumor-infiltrating T lymphocytes (TIL) and in cultured, activated human peripheral blood-derived lymphocytes. No responses were seen in human neutrophils, monocytes, or Epstein-Barr virus-transformed B lymphoblastoid cell lines. rHuMig was chemotactic for TIL by a modified Boyden chamber assay but rHuMig was not chemotactic for neutrophils or monocytes. The CHO cell lines, IFN-~/-treated human peripheral-blood monocytes, and IFN-~/-treated cells of the human monocytic cell line THP-1 all secreted multiple and identical HuMig species as revealed by SDS-PAGE. Using the CHO-derived rHuMig, we have shown that the species' heterogeneity is due to proteolytic cleavage at basic carboxy-terminal residues, and that the proteolysis occurs before and not after rHuMig secretion by the CHO cells. The major species of secreted rHuMig ranged from 78 to 103 amino acids in length, the latter corresponding to the full-length secreted protein predicted from the HuMig cDNA. Carboxy-terminal-truncated forms ofrHuMig were of lower specific activity compared to full-length rHuMig in the calcium flux assay, and the truncated species did not block the activity of the full-length species. It is likely that HuMig plays a role in T cell trafficking and perhaps in other aspects of the physiology of activated T cells.

Chemokine Expression Dynamics in Mycobacterial (Type-1) and Schistosomal (Type-2) Antigen-Elicited Pulmonary Granuloma Formation

“…Of the CKs examined, MIG was highly dependent on IFN-␥, which was predictable based on its known relationship to this cytokine. 32,33 Surprising was the degree of specificity because the other known IFN-␥-induced CK, IP-10, was not dependent. However, it is known that other IFNs can induce IP-10 25 and our finding is consistent with studies of toxoplasma and vaccinia infections, which show differential regulation of MIG and IP-10 with IFN-␥ independence of the latter.…”

“…26,32 Both MIG and IP-10 are chemotactic for NK cells and activated T lymphocytes in vitro, but not resting T cells, B cells, or neutrophils. [32][33][34][35][36] Moreover, IP-10 or MIG expression has been detected in a number of disease conditions with increased expression of IFN-␥ such as psoriasis, 18 tuberculoid leprosy, 19 sarcoidosis, 17 tuberculosis, 16 viral meningitis, 37 leishmaniasis, 14 toxoplasmosis, 38 ulcerative colitis, 15 and nephritic nephrosis. 39 Thus, IP-10 and MIG may provide good markers for Th1 or other interferon-dominant responses as suggested by Dixon and colleagues.…”

Cytotoxic T Lymphocytes Block Tumor Growth Both by Lytic Activity and IFNγ-Dependent Cell-Cycle Arrest

“…It enhances tumor immunogenicity by upregulating components of the MHC antigen processing and presentation pathway. It also induces the expression of chemokines, including the angiostatic chemokines CXCL9 (MIG), CXCL10 (IP-10), and CXCL11 (I-TAC), that block neovascularization in the tumor and recruit effector immune cells (17)(18)(19). Furthermore, IFNg has been reported to exert antiproliferative effects on the developing tumor (20,21), and it triggers apoptosis of tumor cells by inducing proapoptotic molecules (22,23).…”

Chemokine Gene Expression and Clonal Analysis of B Cells in Tissues Involved by Lymphoid Interstitial Pneumonitis from HIV-Infected Pediatric Patients

“…We also observed IFN-␥ mRNA expression in LIP tissues from pediatric HIVinfected patients that was absent in control normal lung tissues from non-HIV infected patients. However, in addition, we showed increased production of IFN-␥-inducible molecules such as IP-10 and Mig that are chemoattractants for T and NK cells (26,27) in LIP tissues compared with control normal lung tissues. A newly discovered molecule, called IGIF (now designated IL-18) with potent IFN-␥-inducing activity (28), was also increased in LIP tissues compared with in normal lung controls, explaining the presence of IFN-␥, IP-10, and Mig.…”