- Email: [email protected]
The CARMA of NF-κB
570
News & Comment
TRENDS in Immunology Vol.23 No.12 December 2002
κB The CARMA of NF-κ The NF-κB family of transcription factors regulates gene expression in activated lymphocytes during the host immune response to bacterial and viral assault, cellular stress and inflammation. For this reason, NF-κB family proteins are favored targets for immunosuppressive therapies. Blocking any aspect of this pathway could effectively block damaging immune responses. What complicates the development of strong inhibitors of these proteins is that in several non-lymphoid tissues, as well as in immature lymphoid cells, NF-κB family proteins are crucial for survival. For example, a systemic NF-κB block would result in liver damage as a result of apoptosis of hepatocytes. Antigen receptors, as well as a host of other stimuli, including cytokine receptors, cell-death receptors and stress signals, activate the NF-κB pathway. In response to all known stimuli, activation of the macromolecular complex known as the IκB–kinase complex, leads to the degradation of IκB and nuclear localization of NF-κB, followed by signal-specific gene expression. How disparate signals activate
the IκB–kinase complex is still unclear. A search for receptor-specific activation of NF-κB previously showed that tumor necrosis factor receptor activated the IκB–kinase complex by a pathway distinct from that initiated at the T-cell receptor (TCR). Furthermore, Bcl10 [a caspase recruitment domain (CARD) containing protein implicated in B-cell lymphoma] and protein kinase C-θ have essential roles in activating the IκB–kinase complex through the TCR. ‘CARMA1 is expressed in lymphoid cells κB–kinase and acts upstream of the Iκ complex, to transmit TCR signals that result κB activation.’ in NF-κ Three recent papers [1–3] identify a CARD domain protein, CARMA1, as a TCR-specific mediator of NF-κB activation. Together these reports show that CARMA1 is expressed in lymphoid cells and acts upstream of the IκB–kinase complex, to transmit TCR signals that result in NF-κB activation. CARMA1 complexes with Bcl10 but the molecular links between CARMA1–Bcl10 and the IκB–kinase
complex remain unclear. The effect of blocking CARMA1 is NF-κB-specific because neither NFAT (nuclear factor of activated T cells) nor AP-1 (activator protein-1), which are activated by the TCR, requires this protein. T-cell functions, such as interleukin-2 (IL-2) secretion, are attenuated providing incentive for targeting CARMA1 as an NF-κB-specific agent for turning off the T-cell response on command. CARMA2, expressed in placenta, and CARMA3, expressed in non-lymphoid tissues, presumably provide similar functions in those cells. 1 Pomerantz, J.L., Denny, E.M. and Baltimore D. (2002) CARD11 mediates factor-specific activation of NF-κB by the T-cell receptor. EMBO J. 21, 5184–5194 2 Wang, D. et al. (2002) A requirement for CARMA1 in TCR-induced NF-κB activation. Nat. Immunol. 3, 830–835 3 Gaide, O. et al. (2002) CARMA1 is a critical lipid raft-assocoated regualtor of TCR-induced NF-κB activation. Nat. Immunol. 3, 836–843
Jyoti Sen [email protected]
In Brief
Pregnancy, hypertension and the immune system The development of high blood pressure in pregnancy is a significant problem in obstetrics and remains a major cause of maternal and fetal morbidity. Several lines of evidence suggest that this hypertension, or eclampsia, has an immunological component arising from a maternal response to fetal antigens. An elegant observation from those working with HIV supports this. In two London hospitals, those mothers with untreated HIV during pregnancy were found to have a lower rate of eclampsia. Treatment of these mothers with triple anti-retroviral therapy increased the rate of eclampsia to that of uninfected mothers. One explanation is that the http://immunology.trends.com
immunocompromise of untreated HIV reduces maternal responses to fetal antigens, whereas anti-retroviral therapy causes an immunological reconstitution, with a more active response. The authors observe also that the anti-retroviral treatment, with its side effects, might exacerbate the development of pregnancy-induced hypertension. Lancet (2002) 360, 1152–1154 CM
Mobile phone text messages could help curb asthma One of the main problems with controlling asthma in young adults is that they forget to take their medication or purposefully skip doses because they resent the idea of their lives revolving around their medication. A team of UK researchers, led by Dr Ron Neville of Westgate Health Centre in Dundee, report that helping young adults better manage their asthma might be as simple as sending asthma-related text messages to their
mobile phones. 30 volunteer Scottish asthmatics, ranging in age (10–46 years), received daily text messages from Max, a ‘virtual friend with asthma’, reminding them to use their inhaler. The study authors claim that the messaging service helped the majority of the study participants to better control their asthma. These findings suggest that text messaging could be used on a national and international scale to help young people manage not only asthma but other diseases as well. Br. Med. J. (2002) 325, 600 SW
Can microchimeras pave the way for macros? A number of approaches are known to facilitate the acceptance of donor marrow. In a careful approach using combinations of treatments, it appears that some success might be claimed by first establishing a microchimera. In a murine model, establishment of a microchimerism of
1471-4906/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.
News & Comment
TRENDS in Immunology Vol.23 No.12 December 2002
κB The CARMA of NF-κ The NF-κB family of transcription factors regulates gene expression in activated lymphocytes during the host immune response to bacterial and viral assault, cellular stress and inflammation. For this reason, NF-κB family proteins are favored targets for immunosuppressive therapies. Blocking any aspect of this pathway could effectively block damaging immune responses. What complicates the development of strong inhibitors of these proteins is that in several non-lymphoid tissues, as well as in immature lymphoid cells, NF-κB family proteins are crucial for survival. For example, a systemic NF-κB block would result in liver damage as a result of apoptosis of hepatocytes. Antigen receptors, as well as a host of other stimuli, including cytokine receptors, cell-death receptors and stress signals, activate the NF-κB pathway. In response to all known stimuli, activation of the macromolecular complex known as the IκB–kinase complex, leads to the degradation of IκB and nuclear localization of NF-κB, followed by signal-specific gene expression. How disparate signals activate
the IκB–kinase complex is still unclear. A search for receptor-specific activation of NF-κB previously showed that tumor necrosis factor receptor activated the IκB–kinase complex by a pathway distinct from that initiated at the T-cell receptor (TCR). Furthermore, Bcl10 [a caspase recruitment domain (CARD) containing protein implicated in B-cell lymphoma] and protein kinase C-θ have essential roles in activating the IκB–kinase complex through the TCR. ‘CARMA1 is expressed in lymphoid cells κB–kinase and acts upstream of the Iκ complex, to transmit TCR signals that result κB activation.’ in NF-κ Three recent papers [1–3] identify a CARD domain protein, CARMA1, as a TCR-specific mediator of NF-κB activation. Together these reports show that CARMA1 is expressed in lymphoid cells and acts upstream of the IκB–kinase complex, to transmit TCR signals that result in NF-κB activation. CARMA1 complexes with Bcl10 but the molecular links between CARMA1–Bcl10 and the IκB–kinase
complex remain unclear. The effect of blocking CARMA1 is NF-κB-specific because neither NFAT (nuclear factor of activated T cells) nor AP-1 (activator protein-1), which are activated by the TCR, requires this protein. T-cell functions, such as interleukin-2 (IL-2) secretion, are attenuated providing incentive for targeting CARMA1 as an NF-κB-specific agent for turning off the T-cell response on command. CARMA2, expressed in placenta, and CARMA3, expressed in non-lymphoid tissues, presumably provide similar functions in those cells. 1 Pomerantz, J.L., Denny, E.M. and Baltimore D. (2002) CARD11 mediates factor-specific activation of NF-κB by the T-cell receptor. EMBO J. 21, 5184–5194 2 Wang, D. et al. (2002) A requirement for CARMA1 in TCR-induced NF-κB activation. Nat. Immunol. 3, 830–835 3 Gaide, O. et al. (2002) CARMA1 is a critical lipid raft-assocoated regualtor of TCR-induced NF-κB activation. Nat. Immunol. 3, 836–843
Jyoti Sen [email protected]
In Brief
Pregnancy, hypertension and the immune system The development of high blood pressure in pregnancy is a significant problem in obstetrics and remains a major cause of maternal and fetal morbidity. Several lines of evidence suggest that this hypertension, or eclampsia, has an immunological component arising from a maternal response to fetal antigens. An elegant observation from those working with HIV supports this. In two London hospitals, those mothers with untreated HIV during pregnancy were found to have a lower rate of eclampsia. Treatment of these mothers with triple anti-retroviral therapy increased the rate of eclampsia to that of uninfected mothers. One explanation is that the http://immunology.trends.com
immunocompromise of untreated HIV reduces maternal responses to fetal antigens, whereas anti-retroviral therapy causes an immunological reconstitution, with a more active response. The authors observe also that the anti-retroviral treatment, with its side effects, might exacerbate the development of pregnancy-induced hypertension. Lancet (2002) 360, 1152–1154 CM
Mobile phone text messages could help curb asthma One of the main problems with controlling asthma in young adults is that they forget to take their medication or purposefully skip doses because they resent the idea of their lives revolving around their medication. A team of UK researchers, led by Dr Ron Neville of Westgate Health Centre in Dundee, report that helping young adults better manage their asthma might be as simple as sending asthma-related text messages to their
mobile phones. 30 volunteer Scottish asthmatics, ranging in age (10–46 years), received daily text messages from Max, a ‘virtual friend with asthma’, reminding them to use their inhaler. The study authors claim that the messaging service helped the majority of the study participants to better control their asthma. These findings suggest that text messaging could be used on a national and international scale to help young people manage not only asthma but other diseases as well. Br. Med. J. (2002) 325, 600 SW
Can microchimeras pave the way for macros? A number of approaches are known to facilitate the acceptance of donor marrow. In a careful approach using combinations of treatments, it appears that some success might be claimed by first establishing a microchimera. In a murine model, establishment of a microchimerism of
1471-4906/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.