The human complement regulatory factor-H-like protein 1, which represents a truncated form of factor H, displays cell-attachment activity

Hellwage, Jens; Kühn, Sabine; Zipfel, Peter F.

doi:10.1042/bj3260321

Cited by 80 publications

(74 citation statements)

References 38 publications

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“…In our study, we demonstrate that H2 cells produce factor H and FHL-1 constitutively in the absence of cytokine stimulation and that both proteins play a role in complement resistance. Because FHL-1 shares the complement-regulating functions with factor H and contains domains relevant for cell attachment (28,29), it can be suggested that FHL-1 also protects H2 cells against complement activation. The higher relative proportion of FHL-1, as compared with factor H, in the H2 cell growth supernatant suggests that FHL-1 may even be more important than factor H.…”

Section: Discussionmentioning

confidence: 99%

“…We observed that the H2 cells themselves synthesized and secreted factor H, as well as the factor H-like protein 1 (FHL-1), a truncated but functionally active form of factor H composed of seven (of 20) N-terminal SCRs of factor H (28,29). FHL-1 is a product of alternative splicing of the factor H gene and has essentially the same functions (cofactor activity and decay-accelerating activity) as factor H (28, 30, 31).…”

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confidence: 99%

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Exceptional Resistance of Human H2 Glioblastoma Cells to Complement-Mediated Killing by Expression and Utilization of Factor H and Factor H-Like Protein 1

Junnikkala

Jokiranta

Friese

et al. 2000

The Journal of Immunology

111

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Of over 20 nucleated cell lines we have examined to date, human H2 glioblastoma cells have turned out to be the most resistant to complement-mediated cytolysis in vitro. H2 cells expressed strongly the membrane attack complex inhibitor protectin (CD59), moderately CD46 (membrane cofactor protein) and CD55 (decay-accelerating factor), but no CD35 (complement receptor 1). When treated with a polyclonal anti-H2 Ab, anti-CD59 mAb, and normal human serum, only 5% of H2 cells became killed. Under the same conditions, 70% of endothelial-like EA.hy 926 cells and 40% of U251 control glioma cells were killed. A combined neutralization of CD46, CD55, and CD59 increased H2 lysis only minimally, demonstrating that these complement regulators are not enough to account for the resistance of H2 cells. After treatment with Abs and serum, less C5b-9 was deposited on H2 than on U251 and EA.hy 926 cell lines. A reason for the exceptional resistance of H2 cells was revealed when RT-PCR and protein biochemical methods showed that the H2 cells, unlike the other cell lines tested, actively produced the soluble complement inhibitors factor H and factor H-like protein 1. H2 cells were also capable of binding human factor H from the fluid phase to their cell surface and promoted the cleavage of C3b to its inactive form iC3b more efficiently than U251 and EA.hy 926 cells. In accordance, anti-factor H mAbs enhanced killing of H2 glioblastoma cells. Taken together, our results show that production and binding of factor H and factor H-like protein 1 is a novel mechanism that these malignant cells utilize to escape complement-mediated killing.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Exceptional Resistance of Human H2 Glioblastoma Cells to Complement-Mediated Killing by Expression and Utilization of Factor H and Factor H-Like Protein 1

Junnikkala

Jokiranta

Friese

et al. 2000

The Journal of Immunology

111

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“…FHL-1 has essentially the same C inhibiting functions (cofactor activity, inhibition of factor B binding and decay accelerating activity) as factor H (Kühn et al, 1995;Kühn and Zipfel, 1996;Hellwage et al, 1997). In the present study our aim was to examine whether human tumour cells secrete soluble C inhibitors that promote C3b inactivation.…”

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confidence: 94%

“…FHL-1 is an alternatively spliced product of the factor H gene, composed of seven N-terminal SCRs of factor H plus an additional four amino acids (Hellwage et al, 1997;Zipfel and Skerka, 1999). FHL-1 has essentially the same C inhibiting functions (cofactor activity, inhibition of factor B binding and decay accelerating activity) as factor H (Kühn et al, 1995;Kühn and Zipfel, 1996;Hellwage et al, 1997).…”

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confidence: 99%

Secretion of soluble complement inhibitors factor H and factor H-like protein (FHL-1) by ovarian tumour cells

et al. 2002

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We observed that the soluble complement regulators factor H and factor H-like protein were abundantly present in ascites samples as well as in primary tumours of patients with ovarian cancer. RT -PCR and immunoblotting analyses showed that the two complement inhibitors were constitutively produced by the ovarian tumour cell lines SK-OV-3 and Caov-3, but not PA-1 or SW626 cells. The amounts of factor H-like protein secreted were equal to those of factor H. This is exceptional, because e.g. in normal human serum the concentration of factor H-like protein is below 1/10th of that of factor H. In ascites samples the mean level of factor H-like protein (130+55 mg ml 71 ) was 5.5-fold higher than in normal human serum (24+3 mg ml 71 ). Ovarian tumour cells thus preferentially synthesise factor H-like protein, the alternatively spliced short variant of factor H. The tumour cells were found to bind both 125 I-labelled factor H and recombinant factor H-like protein to their surfaces. Surprisingly, the culture supernatants of all of the ovarian tumour cell lines studied, including those of PA-1 and SW626 that did not produce factor H/factor H-like protein, promoted factor I-mediated cleavage of C3b to inactive iC3b. Subsequently, the PA-1 and SW626 cell lines were found to secrete a soluble form of the membrane cofactor protein (CD46). Thus, our studies reveal two novel complement resistance mechanisms of ovarian tumour cells: (i) production of factor H-like protein and factor H and (ii) secretion of soluble membrane cofactor protein. Secretion of soluble complement inhibitors could protect ovarian tumour cells against humoral immune attack and pose an obstacle for therapy with monoclonal antibodies.

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“…As a truncated splicing form of the FH-specific mRNA, it comprises the SCR 1-7 (Schwaeble et al, 1987(Schwaeble et al, , 1991 and is present in human serum at concentrations of 20 to 50 g/ml. As does FH, FHL-1 acts as a cofactor of FI for C3b/C4b cleaving (Misasi et al, 1989) and also promotes the dissociation of the C3bBb complex (Kühn et al, 1995) in addition to having some unique biologic functions (Hellwage et al, 1997;Johnsson et al, 1998). The primary site of synthesis of FH is the liver (Zipfel and Skerka, 1994).…”

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confidence: 99%

Constitutive Expression and Regulation of Rat Complement Factor H in Primary Cultures of Hepatocytes, Kupffer Cells, and Two Hepatoma Cell Lines

Schlaf

Beisel

Pollok-Kopp

et al. 2002

Laboratory Investigation

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SUMMARY:The 155-kd soluble complement regulator factor H (FH), which consists of 20 short consensus repeats, increases the affinity of complement factor I (FI) for C3b by about 15 times. In addition to its cofactor activity, it prevents factor B from binding to C3b and promotes the dissociation of the C3bBb complex. The primary site of synthesis of FH, as well as of FI, is the liver, but the cell types responsible for the hepatic synthesis of both factors have not yet been clearly identified. In contrast to FI-mRNA, which was detectable only in hepatocytes (HC), FH-specific mRNA was identified in both HC and Kupffer cells (KC). As calculated for equal amounts of mRNA isolated from both cell types, FH-specific mRNA was found to be nearly 10-fold higher in KC than in HC, leading to the conclusion that KC are an abundant source of FH. Of the investigated proinflammatory cytokines IL-6, TNF-␣, IL-1␤, and IFN-␥, only IFN-␥ up-regulated FH-specific mRNA up to 6-fold in both primary HC and KC. This was also demonstrable on the protein level. However, FH-specific mRNA was not inducible in the rat hepatoma cell line H4IIE, which did not express FH-specific mRNA and could not be up-regulated in FAO cells that constitutively expressed FH-specific mRNA. This demonstrates that transformed cell lines do not reflect FH regulation in isolated primary HC. In addition to IFN-␥, the endotoxin lipopolysaccharide (LPS) up-regulated FH-specific mRNA nearly 10-fold in KC after stimulation at concentrations of 10 or 1 ng/ml. In contrast, concentrations of up to 2 g LPS/ml did not show any effect on HC. Our data suggest that LPS does not regulate the expression of FH in HC. (Lab Invest 2002, 82:183-192).T he regulation of complement activation at the level of C3 and C4 is mediated by several receptors and soluble regulatory proteins. These include complement receptor 1 (CD35), complement receptor 2 (CD21), decay-accelerating factor (CD55), membrane cofactor protein (CD46), factor I (FI), and factor H (FH). These proteins, with the exception of FI, form the "regulators of complement activation" family (Hourcade et al, 1989). Their genes are closely linked on chromosome 1 in man and mouse. This illustrates that this region on the long arm of chromosome 1 in humans is analogous to that region in mice (Klickstein et al, 1985). The serine protease FI could be located to chromosome 4 in man (Goldberger et al, 1987) and to chromosome 3 in mouse (Minta et al, 1996).The potentially deleterious complement system is strictly regulated to prevent damage in the absence of pathologic situations Mulligan et al, 1992;Piddlesden et al, 1994;Smith et al, 1993). On some host cell surfaces, membrane-bound complement regulatory factors are expressed only at low levels. Thus, reduced protection against complement attack may be compensated by the soluble regulator FH, which has a critical role in complement inactivation in the fluid phase (Meri and Pangburn, 1990; Pangburn and Müller-Eberhardt, 1978) and acts in concert with FI. FH is a single-chain protein...

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The human complement regulatory factor-H-like protein 1, which represents a truncated form of factor H, displays cell-attachment activity

Cited by 80 publications

References 38 publications

Exceptional Resistance of Human H2 Glioblastoma Cells to Complement-Mediated Killing by Expression and Utilization of Factor H and Factor H-Like Protein 1

Exceptional Resistance of Human H2 Glioblastoma Cells to Complement-Mediated Killing by Expression and Utilization of Factor H and Factor H-Like Protein 1

Secretion of soluble complement inhibitors factor H and factor H-like protein (FHL-1) by ovarian tumour cells

Constitutive Expression and Regulation of Rat Complement Factor H in Primary Cultures of Hepatocytes, Kupffer Cells, and Two Hepatoma Cell Lines

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