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The Biological Function of the LPS Gene

David L. Rosenstreich

Laboratory of Microbiology and Immunology
National Institute of Dental Research
National Institutes of Health
Bethesda, Maryland

C3H/HeJ mice are resistant or poorly responsive to all the known biological effects of endotoxin (reviewed in 1). This defect is due to a mutation in a single gene that occurred some time between 1960 and 1965 ( 2). The LPS gene has been mapped to the fourth chromosome near the gene that codes for brown coat color ( b) ( 3), and exhibits co-dominant inheritance, so that F1 hybrid progeny of a cross between C3H/HeJ mice with an LPS-responsive strain are intermediate responders to LPS ( 2).

Although LPS exhibit activity in a variety of cellular and humoral systems, it is thought that the primary expression of the LPS gene is in cells since the B-lymphocytes, T-lymphocytes, macrophages ( 1), and fibroblasts ( 4) of C3H/HeJ mice all respond abnormally to LPS in vitro, while at least one humoral function, LPS-induced complement activation, is normal in these mice ( 5). Since a single gene mutation has resulted in the complete loss of LPS-sensitivity in these mice, and since this mutation seems to be expressed only in cells, it is very likely that all the biological effects of LPS are in fact mediated via the action of endotoxin on some cell or cells.

We were interested in understanding the biological role of the LPS gene, and one approach to this question was to determine the ability of C3H/HeJ mice to deal with a variety of challenges such as viruses, bacteria, or malignant cells.

Mice are susceptible to lethal challenge with Herpes simplex virus-1 (HSV-1). Surprisingly, we found that approximately 100 times more HSV-1 was required to kill a C3H/HeJ than was required to kill a C3H/HeN mouse ( 6). This resistance was related to the inability of HSV-1 to grow within C3H/HeJ peritoneal cells since there was no difference in susceptibility of these strains when HSV-1 was innoculated intracerebrally.

In contrast, we have found that C3H/HeJ mice are remarkably susceptible to lethal injection with Salmonella typhimurium. C3H/HeJ mice will die after inoculation with approximately 1,000 times fewer S. typhimurium organisms than are required to kill C3H/HeN mice.

Macrophages will kill tumor cells in vitro if they are obtained from mice infected with organisms such as the BCG strain of Mycobacterium tuberculosis. However, macrophages from BCG-infected C3H/HeJ mice are not tumoricidal, in contrast to those from C3H/HeN mice ( 7). Furthermore, we have found that the ability of macrophages to be rendered tumoricidal is controlled by the LPS gene ( 8).

Thus, in addition to their well characterized defect in LPS-responsiveness, C3H/HeJ mice appear to respond differently to a number of environmental challenges that are unrelated to the exogenous administration of endotoxin ( Table 1). These findings raise an interesting question in relation to the true biological function of the LPS gene. One possible explanation is that endotoxin is a ubiquitous compound whose presence is required by living organisms to maintain the immune system in an "activated" state. If this were the case, then the lymphoreticular cells of C3H/HeJ mice would normally be less "activated" than those of other LPS-responsive mice. This could certainly account for their inability to kill tumor cells, replicate HSV, or adequately kill gram-negative organisms. On the other hand, the LPS molecule itself may be unrelated to this phenomenon. The true function of the LPS gene may be to regulate the activated state of lymphoreticular cells possibly via some serum component that is similar to LPS in structure.


1. Rosenstreich, D.L., Glode, L.M., Wahl, L.M., Sandberg, A.L., and Mergenhagen, S.E. (1977). In Microbiology 1977 (D. Schlessinger, ed.), p. 314. ASM, Washington, D.C.

2. Glode, L.M., and Rosenstreich, D.L. (1976). J. Immunol. 117: 2061.
See also MGI.

3. Watson, J., Kelly, K., Largen, M., and Taylor, B.A. (1974). J. Immunol. 120: 422.

4. Ryan, J.L., and McAdam, K.P.W.J. (1977). Nature 269: 153.
See also MGI.

5. Moeller, G.L., Terry, L., and Snyderman, R. (1978). J. Immunol. 120: 116.
See also MGI.

6. Kirchner, H., Hirt, H.M., Rosenstreich, D.L., and Mergenhagen, S.E. (1978). Proc. Soc. Exp. Med. Biol. 157: 29.
See also MGI.

7. Ruco, L.P., and Meltzer, M.S. (1978). J. Immunol. 120: 329.
See also PubMed.

8. Ruco, L.P., Meltzer, M.S., and Rosenstreich, D.L. (1978). J. Immunol. 121: 523.
See also MGI.

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