Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Reciprocal CD40 signals through p38MAPK and ERK-1/2 induce counteracting immune responses

An Erratum to this article was published on 01 July 2004

Abstract

Macrophages play host to Leishmania major, a parasite that causes leishmaniasis in 500,000 people annually. Macrophage-expressed CD40, a costimulatory molecule1, induces interleukin-12 (IL-12)-dependent and interferon-γ (IFN-γ)-dependent host-protective immune responses to Leishmania and other intracellular pathogens2,3,4,5,6. Paradoxically, IL-10, another CD40-induced cytokine in macrophages7, promotes Leishmania infection8. How CD40 signaling regulates the secretion of these two counteractive cytokines remains unknown. Here we show that weak CD40 signals induce extracellular stress–related kinase-1/2 (ERK-1/2)-dependent IL-10 expression, whereas stronger signals induce p38 mitogen-activated protein kinase (p38MAPK)-dependent IL-12 production. p38MAPK and ERK-1/2 therefore have counter-regulatory actions. Leishmania skews CD40 signaling toward ERK-1/2, inducing IL-10, which inhibits activation of CD40-induced p38MAPK and expression of inducible nitric oxide synthase-2 (iNOS-2) and IL-12. ERK-1/2 inhibition or IL-10 neutralization restores CD40-induced p38MAPK activation and parasite killing in macrophages and the BALB/c mouse, a susceptible host. These data uncover a new immune evasion strategy, whereby Leishmania differentially modulates CD40-engaged, reciprocally functioning signaling modules, and provide a new conceptual framework for immune homeostasis.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Leishmania regulates CD40 signaling through p38MAPK- and CD40-induced effector functions in macrophages.
Figure 2: CD40-induced p38MAPK and ERK-1/2 regulate each other reciprocally, affecting their respective effector functions.
Figure 3: IL-10 neutralization and ERK-1/2 inhibition restore CD40-induced p38MAPK phosphorylation and restrict parasite growth in vitro.
Figure 4: In a susceptible host, ERK-1/2 inhibition ameliorates Leishmania infection and reinstates TH1 response.

References

  1. Grewal, I.S. & Flavell, R.A. CD40 and CD154 in cell-mediated immunity. Annu. Rev. Immunol. 16, 111–135 (1998).

    Article  CAS  Google Scholar 

  2. Samten, B. et al. CD40 ligand trimer enhances the response of CD8+ T cells to Mycobacterium tuberculosis. J. Immunol. 170, 3180–3186 (2003).

    Article  CAS  Google Scholar 

  3. Speirs, K., Caamano, J., Goldschmidt, M.H., Hunter, C.A. & Scott, P. NF-κB2 is required for optimal CD40-induced IL-12 production but dispensable for Th1 cell differentiation. J. Immunol. 168, 4406–4413 (2002).

    Article  CAS  Google Scholar 

  4. Xu, D. et al. Protective effect on Leishmania major infection of migration inhibitory factor, TNF-α, and IFN-γ administered orally via attenuated Salmonella typhimurium. J. Immunol. 160, 1285–1289 (1998).

    CAS  PubMed  Google Scholar 

  5. Kamanaka, M. et al. Protective role of CD40 in Leishmania major infection at two distinct phases of cell-mediated immunity. Immunity 4, 275–281 (1996).

    Article  CAS  Google Scholar 

  6. Heinzel, F.P., Rerko, R.M. & Hujer, A.M. Underproduction of interleukin-12 in susceptible mice during progressive leishmaniasis is due to decreased CD40 activity. Cell. Immunol. 184, 129–142 (1998).

    Article  CAS  Google Scholar 

  7. Foey, A.D., Feldmann, M. & Brennan, F.M. Route of monocyte differentiation determines their cytokine production profile: CD40 ligation induces interleukin 10 expression. Cytokine 12, 1496–1505 (2000).

    Article  CAS  Google Scholar 

  8. Groux, H. et al. A transgenic model to analyze the immunoregulatory role of IL-10 secreted by antigen-presenting cells. J. Immunol. 162, 1723–1729 (1999).

    CAS  PubMed  Google Scholar 

  9. Dong, C. & Flavell, R.A. Th1 and Th2 cells. Curr. Opin. Hematol. 8, 47–51 (2001).

    Article  CAS  Google Scholar 

  10. Mosmann, T.R. & Moore, K.W. The role of IL-10 in cross-regulation of Th1 and Th2 responses. Immunol. Today 12, A49–A53 (1991).

    Article  CAS  Google Scholar 

  11. Liew, F.Y. Functional heterogeneity of CD4+ T cells in leishmaniasis. Immunol. Today 10, 40–45 (1989).

    Article  CAS  Google Scholar 

  12. Scott, P. Differentiation, regulation, and death of T helper cell subsets during infection with Leishmania major. Immunol. Res. 17, 229–238 (1998).

    Article  CAS  Google Scholar 

  13. Reiner, S.L. & Locksley, R.M. The regulation of immunity to L. major. Annu. Rev. Immunol. 13, 151–177 (1995).

    Article  CAS  Google Scholar 

  14. Cano, E. & Mahadevan, L.C. Parallel signal processing among mammalian MAPKs. Trends Biochem. Sci. 20, 117–122 (1995).

    Article  CAS  Google Scholar 

  15. Clayton, A.L. & Mahadevan, L.C. MAP kinase-mediated phosphoacetylation of histone H3 and inducible gene regulation. FEBS Lett. 546, 51–58 (2003).

    Article  CAS  Google Scholar 

  16. Feng, G.J. et al. Extracellular signal-related kinase (ERK) and p38 mitogen-activated protein (MAP) kinases differentially regulate the LPS-mediated induction of inducible nitric oxide synthase and IL-12 in macrophages: Leishmania phosphoglycans subvert macrophage IL-12 production by targeting ERK MAP kinase. J. Immunol. 163, 6403–6412 (1999).

    CAS  PubMed  Google Scholar 

  17. Lu, H.-T. et al. Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. EMBO J. 18, 1845–1857 (1999).

    Article  CAS  Google Scholar 

  18. Yi, A.K. et al. Role of mitogen-activated protein kinases in CpG DNA-mediated IL-10 and IL-12 production: central role of extracellular signal-regulated kinase in the negative feedback loop of the CpG DNA-mediated Th1 response. J. Immunol. 168, 4711–4720 (2002).

    Article  CAS  Google Scholar 

  19. Awasthi, A. et al. CD40 signaling is impaired in L. major-infected macrophages and is rescued by a p38MAPK activator establishing a host-protective memory T cell response. J. Exp. Med. 197, 1037–1043 (2003).

    Article  CAS  Google Scholar 

  20. Carrera, L. et al. Leishmania promastigotes selectively inhibit IL-12 induction in bone-marrow-derived macrophages from susceptible and resistant mice. J. Exp. Med. 183, 515–526 (1996).

    Article  CAS  Google Scholar 

  21. Belkaid, Y., Butcher, B. & Sacks, D.L. Analysis of cytokine production by inflammatory mouse macrophages at the single-cell level: selective impairment of IL-12 induction in Leishmania-infected cells. Eur. J. Immunol. 28, 1389–1400 (1998).

    Article  CAS  Google Scholar 

  22. Sutterwala, F.S., Noel, G.J., Clynes, R. & Mosser, D.M. Selective suppression of interleukin-12 induction after macrophage receptor ligation. J. Exp. Med. 185, 1977–1985 (1997).

    Article  CAS  Google Scholar 

  23. Crawley, J.B. et al. T cell proliferation in response to interleukins 2 and 7 requires p38MAP kinase activation. J. Biol. Chem. 272, 15023–15027 (1997).

    Article  CAS  Google Scholar 

  24. Watts, S.W. Serotonin activates the mitogen-activated protein kinase pathway in vascular smooth muscle: use of the mitogen-activated protein kinase kinase inhibitor PD098059. J. Pharmacol. Exp. Ther. 279, 1541–1550 (1996).

    CAS  PubMed  Google Scholar 

  25. Belkaid, Y. et al. The role of interleukin (IL)-10 in the persistence of Leishmania major in the skin after healing and the therapeutic potential of IL-10-specific receptor antibody for sterile cure. J. Exp. Med. 194, 1497–1506 (2001).

    Article  CAS  Google Scholar 

  26. Padigel, U.M., Alexander, J. & Farrell, J.P. The role of interleukin-10 in susceptibility of BALB/c mice to infection with Leishmania mexicana and Leishmania amazonensis. J. Immunol. 171, 3705–3710 (2003).

    Article  CAS  Google Scholar 

  27. Krummel, M.F. & Allison, J.P. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J. Exp. Med. 182, 459–465 (1995).

    Article  CAS  Google Scholar 

  28. Tachimoto, H. et al. Reciprocal regulation of cultured human mast cells cytokine production by IL-4 and IFN-γ. J. Allergy Clin. Immunol. 106, 141–149 (2000).

    Article  CAS  Google Scholar 

  29. Park, S.J. et al. Opposite role of Ras in tumor necrosis factor-α-induced cell cycle regulation: competition for Raf kinase. Biochem. Biophys. Res. Commun. 287, 1140–1147 (2001).

    Article  CAS  Google Scholar 

  30. Hermiston, M.L., Xu, Z. & Weiss, A. CD45: a critical regulator of signaling thresholds in immune cells. Annu. Rev. Immunol. 21, 107–137 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the Department of Science and Technology, Department of Biotechnology, Indian Council of Medical Research, Council of Scientific and Industrial Research and Life Science Research Board, Government of India.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Bhaskar Saha.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Mathur, R., Awasthi, A., Wadhone, P. et al. Reciprocal CD40 signals through p38MAPK and ERK-1/2 induce counteracting immune responses. Nat Med 10, 540–544 (2004). https://doi.org/10.1038/nm1045

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1045

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing